Comparison of US Federal and Foundation Funding of Research for Sickle Cell Disease and Cystic Fibrosis and Factors Associated With Research Productivity | Adolescent Medicine | JAMA Network Open | JAMA Network
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Figure 1.  Number of Disease-Specific PubMed Listings and US Food and Drug Administration Drug Approvals Over Time
Number of Disease-Specific PubMed Listings and US Food and Drug Administration Drug Approvals Over Time

CF indicates cystic fibrosis; SCD, sickle cell disease.

Figure 2.  Progression of Life Span for Cystic Fibrosis (CF) and Sickle Cell Disease (SCD) and Major Health Care Milestones
Progression of Life Span for Cystic Fibrosis (CF) and Sickle Cell Disease (SCD) and Major Health Care Milestones

Life Span graphs adapted from Wailoo29 and Elborn.30 ALL indicates acute lymphocytic leukemia; CFF, Cystic Fibrosis Foundation; HSCT, hematopoietic stem cell transplant; and NIH, National Institutes of Health.

Table 1.  Summary of Disease Characteristics, Funding, and Research Output
Summary of Disease Characteristics, Funding, and Research Output
Table 2.  Disease-Specific NIH Funding and Combined Foundation Expenditures
Disease-Specific NIH Funding and Combined Foundation Expenditures
Table 3.  Annual Number of US-Based Interventional Clinical Trials Listed on ClinicalTrials.gov by Funding Source
Annual Number of US-Based Interventional Clinical Trials Listed on ClinicalTrials.gov by Funding Source
1.
Centers for Disease Control and Prevention.  Data & Statistics on Sickle Cell Disease. Centers for Disease Control and Prevention; 2017.
2.
Lin  JH, Collaco  JM, Paranjape  SM.  Cystic fibrosis in a Hispanic adolescent.  Pediatr Pulmonol. 2014;49(3):E40-E41. doi:10.1002/ppul.22758PubMedGoogle ScholarCrossref
3.
Spoonhower  KA, Davis  PB.  Epidemiology of cystic fibrosis.  Clin Chest Med. 2016;37(1):1-8. doi:10.1016/j.ccm.2015.10.002PubMedGoogle ScholarCrossref
4.
Herrick  JB.  Peculiar elongated and sickle-shaped red blood corpuscles in a case of severe anemia.  JAMA. 2014;312(10):1063. doi:10.1001/jama.2014.11011PubMedGoogle ScholarCrossref
5.
Pauling  L, Itano  HA, Singer  SJ, Wells  IC.  Sickle cell anemia a molecular disease.  Science. 1949;110(2865):543-548. doi:10.1126/science.110.2865.543PubMedGoogle ScholarCrossref
6.
Ingram  VM.  Abnormal human haemoglobins, I: the comparison of normal human and sickle-cell haemoglobins by fingerprinting.  Biochim Biophys Acta. 1958;28(3):539-545. doi:10.1016/0006-3002(58)90516-XPubMedGoogle ScholarCrossref
7.
Beutler  E.  The effect of methemoglobin formation in sickle cell disease.  J Clin Invest. 1961;40(10):1856-1871. doi:10.1172/JCI104410PubMedGoogle ScholarCrossref
8.
Scott  RB.  Health care priority and sickle cell anemia.  JAMA. 1970;214(4):731-734. doi:10.1001/jama.1970.03180040039008PubMedGoogle ScholarCrossref
9.
Scott  RB.  Sickle-cell anemia: high prevalence and low priority.  N Engl J Med. 1970;282(3):164-165. doi:10.1056/NEJM197001152820312PubMedGoogle ScholarCrossref
10.
Andersen  DH.  Cystic fibrosis of the pancreas and its relation to celiac disease: a clinical and pathologic study.  AJDC. 1938;56(2):344-399. doi:10.1001/archpedi.1938.01980140114013Google Scholar
11.
Kerem  B, Rommens  JM, Buchanan  JA,  et al.  Identification of the cystic fibrosis gene: genetic analysis.  Science. 1989;245(4922):1073-1080. doi:10.1126/science.2570460PubMedGoogle ScholarCrossref
12.
Riordan  JR, Rommens  JM, Kerem  B,  et al.  Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA.  Science. 1989;245(4922):1066-1073. doi:10.1126/science.2475911PubMedGoogle ScholarCrossref
13.
Rommens  JM, Iannuzzi  MC, Kerem  B,  et al.  Identification of the cystic fibrosis gene: chromosome walking and jumping.  Science. 1989;245(4922):1059-1065. doi:10.1126/science.2772657PubMedGoogle ScholarCrossref
14.
Ramsey  BW, Davies  J, McElvaney  NG,  et al; VX08-770-102 Study Group.  A CFTR potentiator in patients with cystic fibrosis and the G551D mutation.  N Engl J Med. 2011;365(18):1663-1672. doi:10.1056/NEJMoa1105185PubMedGoogle ScholarCrossref
15.
Wainwright  CE, Elborn  JS, Ramsey  BW,  et al; TRAFFIC Study Group; TRANSPORT Study Group.  Lumacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR.  N Engl J Med. 2015;373(3):220-231. doi:10.1056/NEJMoa1409547PubMedGoogle ScholarCrossref
16.
Taylor-Cousar  JL, Munck  A, McKone  EF,  et al.  Tezacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del.  N Engl J Med. 2017;377(21):2013-2023. doi:10.1056/NEJMoa1709846PubMedGoogle ScholarCrossref
17.
Moses  H  III, Matheson  DH, Cairns-Smith  S, George  BP, Palisch  C, Dorsey  ER.  The anatomy of medical research: US and international comparisons.  JAMA. 2015;313(2):174-189. doi:10.1001/jama.2014.15939PubMedGoogle ScholarCrossref
18.
National Institutes of Health.  Report on NIH Funding vs. Global Burden of Disease. National Institutes of Health; 2018.
19.
Hassell  KL.  Population estimates of sickle cell disease in the U.S.  Am J Prev Med. 2010;38(4)(suppl):S512-S521. doi:10.1016/j.amepre.2009.12.022PubMedGoogle ScholarCrossref
20.
Cystic Fibrosis Foundation.  Patient Registry Annual: Data Report. Cystic Fibrosis Foundation; 2017.
21.
Feuchtbaum  L, Carter  J, Dowray  S, Currier  RJ, Lorey  F.  Birth prevalence of disorders detectable through newborn screening by race/ethnicity.  Genet Med. 2012;14(11):937-945. doi:10.1038/gim.2012.76PubMedGoogle ScholarCrossref
22.
Lorey  FW, Arnopp  J, Cunningham  GC.  Distribution of hemoglobinopathy variants by ethnicity in a multiethnic state.  Genet Epidemiol. 1996;13(5):501-512. doi:10.1002/(SICI)1098-2272(1996)13:5<501::AID-GEPI6>3.0.CO;2-4PubMedGoogle ScholarCrossref
23.
Elmariah  H, Garrett  ME, De Castro  LM,  et al.  Factors associated with survival in a contemporary adult sickle cell disease cohort.  Am J Hematol. 2014;89(5):530-535. doi:10.1002/ajh.23683PubMedGoogle ScholarCrossref
24.
National Institutes of Health.  Estimates of Funding for Various Research, Condition, and Disease Categories (RCDC). National Institutes of Health; 2017.
25.
Kauf  TL, Coates  TD, Huazhi  L, Mody-Patel  N, Hartzema  AG.  The cost of health care for children and adults with sickle cell disease.  Am J Hematol. 2009;84(6):323-327. doi:10.1002/ajh.21408PubMedGoogle ScholarCrossref
26.
van Gool  K, Norman  R, Delatycki  MB, Hall  J, Massie  J.  Understanding the costs of care for cystic fibrosis: an analysis by age and health state.  Value Health. 2013;16(2):345-355. doi:10.1016/j.jval.2012.12.003PubMedGoogle ScholarCrossref
27.
Hassan  M, Bonafede  MM, Limone  BL, Hodgkins  P, Sawicki  GS.  The burden of cystic fibrosis in the Medicaid population.  Clinicoecon Outcomes Res. 2018;10:423-431. doi:10.2147/CEOR.S162021PubMedGoogle ScholarCrossref
28.
US Trust; Indiana University Lilly Family School of Philanthropy. High net worth philanthropy: charitable practices and preferences of wealthy households. October 2016. Accessed February 22, 2020. https://scholarworks.iupui.edu/bitstream/handle/1805/11234/high-net-worth_oct_2017-1.pdf?sequence=4&isAllowed=y
29.
Wailoo  K.  Sickle cell disease—a history of progress and peril.  N Engl J Med. 2017;376(9):805-807. doi:10.1056/NEJMp1700101PubMedGoogle ScholarCrossref
30.
Elborn  JS.  Personalised medicine for cystic fibrosis: treating the basic defect.  Eur Respir Rev. 2013;22(127):3-5. doi:10.1183/09059180.00008112PubMedGoogle ScholarCrossref
31.
National Sickle Cell Anemia Control Act, Pub L No. 92-2941972.
32.
Benson  JM, Therrell  BL  Jr.  History and current status of newborn screening for hemoglobinopathies.  Semin Perinatol. 2010;34(2):134-144. doi:10.1053/j.semperi.2009.12.006PubMedGoogle ScholarCrossref
33.
Scharff  DP, Mathews  KJ, Jackson  P, Hoffsuemmer  J, Martin  E, Edwards  D.  More than Tuskegee: understanding mistrust about research participation.  J Health Care Poor Underserved. 2010;21(3):879-897. doi:10.1353/hpu.0.0323PubMedGoogle ScholarCrossref
34.
Ioannidis  JP, Klavans  R, Boyack  KW.  Multiple citation indicators and their composite across scientific disciplines.  PLoS Biol. 2016;14(7):e1002501. doi:10.1371/journal.pbio.1002501PubMedGoogle Scholar
35.
Dorsey  ER, de Roulet  J, Thompson  JP,  et al.  Funding of US biomedical research, 2003-2008.  JAMA. 2010;303(2):137-143. doi:10.1001/jama.2009.1987PubMedGoogle ScholarCrossref
36.
PhRMA. Biopharmaceutical Research Industry Profile and Toolkit. PhRMA; 2018.
37.
Lanthier  M.  Insights Into Rare Disease Drug Approval: Trends and Recent Developments. US Food and Drug Administration; 2017.
38.
Walker  J, Rockoff  JD. Cystic Fibrosis Foundation sells drugs rights for $3.3 billion: the biggest royalty purchase ever reflects group’s share of Kalydeco sales. Wall Street Journal. November 19, 2014. Accessed February 24, 2020. https://www.wsj.com/articles/cystic-fibrosis-foundation-sells-drugs-rights-for-3-3-billion-1416414300
39.
Seltzer  R. Endowment returns slow: survey offers peek at spending. Inside Higher Ed. January 31, 2019. Accessed February 22, 2020. https://www.insidehighered.com/news/2019/01/31/college-endowments-returned-82-percent-2018-annual-survey-adds-some-insight-how
40.
Johnson  FL, Look  AT, Gockerman  J, Ruggiero  MR, Dalla-Pozza  L, Billings  FT  III.  Bone-marrow transplantation in a patient with sickle-cell anemia.  N Engl J Med. 1984;311(12):780-783. doi:10.1056/NEJM198409203111207PubMedGoogle ScholarCrossref
41.
Platt  OS, Orkin  SH, Dover  G, Beardsley  GP, Miller  B, Nathan  DG.  Hydroxyurea enhances fetal hemoglobin production in sickle cell anemia.  J Clin Invest. 1984;74(2):652-656. doi:10.1172/JCI111464PubMedGoogle ScholarCrossref
42.
O’Reilly  R, Elphick  HE.  Development, clinical utility, and place of ivacaftor in the treatment of cystic fibrosis.  Drug Des Dev Ther. 2013;7:929-937.PubMedGoogle Scholar
43.
Niihara  Y, Koh  HA, Tran  L,  et al.  A phase 3 study of l-glutamine therapy for sickle cell anemia and sickle β0-thalassemia.  Blood. 2014;124(21):86-86. doi:10.1182/blood.V124.21.86.86Google ScholarCrossref
44.
Ribeil  JA, Hacein-Bey-Abina  S, Payen  E,  et al.  Gene therapy in a patient with sickle cell disease.  N Engl J Med. 2017;376(9):848-855. doi:10.1056/NEJMoa1609677PubMedGoogle ScholarCrossref
45.
Ataga  KI, Kutlar  A, Kanter  J,  et al.  Crizanlizumab for the prevention of pain crises in sickle cell disease.  N Engl J Med. 2017;376(5):429-439. doi:10.1056/NEJMoa1611770PubMedGoogle ScholarCrossref
46.
Mall  MA, Mayer-Hamblett  N, Rowe  SM.  Cystic fibrosis: emergence of highly effective targeted therapeutics and potential clinical implications.  Am J Respir Crit Care Med. 2019. doi:10.1164/rccm.201910-1943SOPubMedGoogle Scholar
47.
Niihara  Y, Miller  ST, Kanter  J,  et al; Investigators of the Phase 3 Trial of l-Glutamine in Sickle Cell Disease.  A phase 3 trial of l-glutamine in sickle cell disease.  N Engl J Med. 2018;379(3):226-235. doi:10.1056/NEJMoa1715971PubMedGoogle ScholarCrossref
48.
Heeney  MM, Hoppe  CC, Abboud  MR,  et al; DOVE Investigators.  A multinational trial of prasugrel for sickle cell vaso-occlusive events.  N Engl J Med. 2016;374(7):625-635. doi:10.1056/NEJMoa1512021PubMedGoogle ScholarCrossref
49.
Arnold  SD, Brazauskas  R, He  N,  et al.  Clinical risks and healthcare utilization of hematopoietic cell transplantation for sickle cell disease in the USA using merged databases.  Haematologica. 2017;102(11):1823-1832. doi:10.3324/haematol.2017.169581PubMedGoogle ScholarCrossref
50.
Khemani  K, Ross  D, Sinha  C, Haight  A, Bakshi  N, Krishnamurti  L.  Experiences and decision making in hematopoietic stem cell transplant in sickle cell disease: patients’ and caregivers’ perspectives.  Biol Blood Marrow Transplant. 2018;24(5):1041-1048. doi:10.1016/j.bbmt.2017.11.018PubMedGoogle ScholarCrossref
51.
Shenoy  S, Angelucci  E, Arnold  SD,  et al.  Current results and future research priorities in late effects after hematopoietic stem cell transplantation for children with sickle cell disease and thalassemia: a consensus statement from the Second Pediatric Blood and Marrow Transplant Consortium International Conference on Late Effects After Pediatric Hematopoietic Stem Cell Transplantation.  Biol Blood Marrow Transplant. 2017;23(4):552-561. doi:10.1016/j.bbmt.2017.01.009PubMedGoogle ScholarCrossref
52.
Burney  TJ, Davies  JC.  Gene therapy for the treatment of cystic fibrosis.  Appl Clin Genet. 2012;5:29-36.PubMedGoogle Scholar
53.
Grosse  SD, Schechter  MS, Kulkarni  R, Lloyd-Puryear  MA, Strickland  B, Trevathan  E.  Models of comprehensive multidisciplinary care for individuals in the United States with genetic disorders.  Pediatrics. 2009;123(1):407-412. doi:10.1542/peds.2007-2875PubMedGoogle ScholarCrossref
54.
Robinson  MR, Daniel  LC, O’Hara  EA, Szabo  MM, Barakat  LP.  Insurance status as a sociodemographic risk factor for functional outcomes and health-related quality of life among youth with sickle cell disease.  J Pediatr Hematol Oncol. 2014;36(1):51-56. doi:10.1097/MPH.0000000000000013PubMedGoogle ScholarCrossref
55.
Marshall  BC, Nelson  EC.  Accelerating implementation of biomedical research advances: critical elements of a successful 10 year Cystic Fibrosis Foundation healthcare delivery improvement initiative.  BMJ Qual Saf. 2014;23(suppl 1):i95-i103. doi:10.1136/bmjqs-2013-002790PubMedGoogle ScholarCrossref
56.
National Heart, Lung, and Blood Institute.  Evidence-Based Management of Sickle Cell Disease: Expert Panel Report, 2014. National Heart, Lung, and Blood Institute; 2014.
57.
Stettler  N, McKiernan  CM, Melin  CQ, Adejoro  OO, Walczak  NB.  Proportion of adults with sickle cell anemia and pain crises receiving hydroxyurea.  JAMA. 2015;313(16):1671-1672. doi:10.1001/jama.2015.3075PubMedGoogle ScholarCrossref
58.
Quinn  CT, Rogers  ZR, McCavit  TL, Buchanan  GR.  Improved survival of children and adolescents with sickle cell disease.  Blood. 2010;115(17):3447-3452. doi:10.1182/blood-2009-07-233700PubMedGoogle ScholarCrossref
59.
Konstan  MW, VanDevanter  DR, Sawicki  GS,  et al.  Association of high-dose ibuprofen use, lung function decline, and long-term survival in children with cystic fibrosis.  Ann Am Thorac Soc. 2018;15(4):485-493. doi:10.1513/AnnalsATS.201706-486OCPubMedGoogle ScholarCrossref
60.
Lanzkron  S, Carroll  CP, Haywood  C  Jr.  Mortality rates and age at death from sickle cell disease: U.S., 1979-2005.  Public Health Rep. 2013;128(2):110-116. doi:10.1177/003335491312800206PubMedGoogle ScholarCrossref
61.
Wierenga  KJJ, Hambleton  IR, Lewis  NA; Sickle Cell Unit.  Survival estimates for patients with homozygous sickle-cell disease in Jamaica: a clinic-based population study.  Lancet. 2001;357(9257):680-683. doi:10.1016/S0140-6736(00)04132-5PubMedGoogle ScholarCrossref
62.
Stephenson  AL, Sykes  J, Stanojevic  S,  et al.  Survival comparison of patients with cystic fibrosis in Canada and the United States: a population-based cohort study.  Ann Intern Med. 2017;166(8):537-546. doi:10.7326/M16-0858PubMedGoogle ScholarCrossref
63.
Smedley  BD, Stith  AY, Nelson  AR, eds.  Institute of Medicine Committee on Understanding Eliminating Racial Ethnic Disparities in Health Care. Unequal Treatment: Confronting Racial and Ethnic Disparities in Health Care. National Academies Press; 2002.
64.
 Sickle cell anemia, a race specific disease.  JAMA. 1947;133(1):33-34. doi:10.1001/jama.1947.02880010035011Google Scholar
65.
Wailoo  K, Pemberton  S.  The Troubled Dream of Genetic Medicine: Ethnicity and Innovation in Tay-Sachs, Cystic Fibrosis, and Sickle Cell Disease. Johns Hopkins University Press; 2006.
66.
McGarry  ME, McColley  SA.  Minorities are underrepresented in clinical trials of pharmaceutical agents for cystic fibrosis.  Ann Am Thorac Soc. 2016;13(10):1721-1725. doi:10.1513/AnnalsATS.201603-192BCPubMedGoogle Scholar
67.
Buu  MC, Sanders  LM, Mayo  JA, Milla  CE, Wise  PH.  Assessing differences in mortality rates and risk factors between Hispanic and non-Hispanic patients with cystic fibrosis in California.  Chest. 2016;149(2):380-389. doi:10.1378/chest.14-2189PubMedGoogle ScholarCrossref
68.
Webb Hooper  M, Mitchell  C, Marshall  VJ,  et al.  Understanding multilevel factors related to urban community trust in healthcare and research.  Int J Environ Res Public Health. 2019;16(18):E3280. doi:10.3390/ijerph16183280PubMedGoogle Scholar
69.
Haywood  C  Jr, Lanzkron  S, Bediako  S,  et al; IMPORT Investigators.  Perceived discrimination, patient trust, and adherence to medical recommendations among persons with sickle cell disease.  J Gen Intern Med. 2014;29(12):1657-1662. doi:10.1007/s11606-014-2986-7PubMedGoogle ScholarCrossref
70.
Sinha  CB, Bakshi  N, Ross  D, Krishnamurti  L.  Management of chronic pain in adults living with sickle cell disease in the era of the opioid epidemic: a qualitative study.  JAMA Netw Open. 2019;2(5):e194410. doi:10.1001/jamanetworkopen.2019.4410PubMedGoogle Scholar
71.
Bulgin  D, Tanabe  P, Jenerette  C.  Stigma of sickle cell disease: a systematic review.  Issues Ment Health Nurs. 2018;39(8):675-686. doi:10.1080/01612840.2018.1443530PubMedGoogle ScholarCrossref
72.
Cystic Fibrosis Foundation. Annual report 2018. Accessed February 21, 2020. https://www.cff.org/About-Us/Assets/2018-Annual-Report.pdf
73.
Furlong  P, Bridges  JF, Charnas  L,  et al.  How a patient advocacy group developed the first proposed draft guidance document for industry for submission to the US Food and Drug Administration.  Orphanet J Rare Dis. 2015;10:82. doi:10.1186/s13023-015-0281-2PubMedGoogle ScholarCrossref
74.
Health Resources and Services Administration. Sickle Cell Disease Treatment Demonstration Regional Collaboratives Program. Accessed February 21, 2020. https://www.hrsa.gov/grants/find-funding/hrsa-17-078
75.
Bleich  SN, Findling  MG, Casey  LS,  et al.  Discrimination in the United States: experiences of black Americans.  Health Serv Res. 2019;54(suppl 2):1399-1408. doi:10.1111/1475-6773.13220PubMedGoogle ScholarCrossref
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    Original Investigation
    Health Policy
    March 27, 2020

    Comparison of US Federal and Foundation Funding of Research for Sickle Cell Disease and Cystic Fibrosis and Factors Associated With Research Productivity

    Author Affiliations
    • 1Deparment of Pediatrics and Medicine, Stony Brook University Hospital, Stony Brook, New York
    • 2Division of Pediatric Pulmonology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland
    • 3Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
    • 4Berman Institute of Bioethics, Johns Hopkins University School of Medicine, Baltimore, Maryland
    • 5Division of Hematology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina
    • 6Division of Pediatric Hematology/Oncology, Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina
    JAMA Netw Open. 2020;3(3):e201737. doi:10.1001/jamanetworkopen.2020.1737
    Key Points español 中文 (chinese)

    Question  Are differences in disease-specific funding between sickle cell disease and cystic fibrosis associated with variations in drug development and research publications?

    Findings  This cross-sectional study of research funding and outputs for cystic fibrosis and sickle cell disease found that both federal funding and foundation expenditures were greater for cystic fibrosis compared with sickle cell disease. Significantly more research articles and drug approvals were found for cystic fibrosis compared with sickle cell disease, but the total numbers of clinical trials were similar.

    Meaning  The findings show that disparities in funding exist between sickle cell disease and cystic fibrosis and that these disparities may be associated with decreased research productivity and novel drug development for sickle cell disease.

    Abstract

    Importance  Sickle cell disease (SCD) and cystic fibrosis (CF) are severe autosomal recessive disorders associated with intermittent disease exacerbations that require hospitalizations, progressive chronic organ injury, and substantial premature mortality. Research funding is a limited resource and may contribute to health care disparities, especially for rare diseases that disproportionally affect economically disadvantaged groups.

    Objective  To compare disease-specific funding between SCD and CF and the association between funding and research productivity.

    Design, Setting, and Participants  This cross-sectional study examined federal and foundation funding, publications indexed in PubMed, clinical trials registered in ClinicalTrials.gov, and new drug approvals from January 1, 2008, to December 31, 2018, in an estimated US population of approximately 90 000 individuals with SCD and approximately 30 000 individuals with CF.

    Main Outcomes and Measures  Federal and foundation funding, publications indexed in PubMed, clinical trial registrations, and new drug approvals.

    Results  From 2008 through 2018, federal funding was greater per person with CF compared with SCD (mean [SD], $2807 [$175] vs $812 [$147]; P < .001). Foundation expenditures were greater for CF than for SCD (mean [SD], $7690 [$3974] vs $102 [$13.7]; P < .001). Significantly more research articles (mean [SD], 1594 [225] vs 926 [157]; P < .001) and US Food and Drug Administration drug approvals (4 vs 1) were found for CF compared with SCD, but the total number of clinical trials was similar (mean [SD], 27.3 [6.9] vs 23.8 [6.3]; P = .22).

    Conclusions and Relevance  The findings show that disparities in funding between SCD and CF may be associated with decreased research productivity and novel drug development for SCD. Increased federal and foundation funding is needed for SCD and other diseases that disproportionately affect economically disadvantaged groups to address health care disparities.

    Introduction

    Sickle cell disease (SCD) and cystic fibrosis (CF) are inherited disorders associated with intermittent disease exacerbations that require hospitalizations and with a substantial reduction in the median life span. The US birth rate of SCD is 1 in 365 black individuals, and the US birth rate of CF is 1 in 2500 white individuals.1-3 Initially described in 1910, SCD subsequently became the first disease with a known molecular and genetic mechanism, making it the most thoroughly understood disease of its time.4-7 The initial knowledge of the molecular mechanism of SCD has not effectively translated into many approved therapies, but it has informed newborn screening and supportive care.8,9 In comparison, to our knowledge, CF was first described in the western literature in 1938.10 The genetic variant leading to a cellular membrane protein malfunction was not identified until 1989.11-13 The strategies used to identify the CFTR (OMIM 602421) variant informed techniques for the Human Genome Project and led to the approval of the first targeted therapy to correct the underlying chloride transport variant in 2011.14-16

    National Institutes of Health (NIH) funding generally aligns with disease burden based on disease prevalence, severity, and age at onset. Several publications17,18 have examined the association between disability-adjusted life-years in the US and globally and NIH funding. These studies17,18 reported an association between increased funding for diseases that cause a greater reduction in disability-adjusted life-years. However, complex societal factors contribute to how private medical foundations generate revenue to fund advocacy and research. We assessed whether expenditures by the NIH and the national foundations for these diseases are associated with the number of publications indexed in PubMed, active clinical trials, and US Food and Drug Administration (FDA) drug approvals.

    Methods

    For this cross-sectional study, we analyzed publicly reported metrics of disease funding and indicators of research productivity. This study was deemed to be exempt from institutional review board review based on criteria of the Health and Human Services Common Rule (45 CFR §46) because it did not include data from human participants, and informed consent was not required. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

    We report total NIH funding and career development awards for each disease from January 1, 2008, to December 31, 2017, using the NIH Report database. For funding from foundations, we reviewed publicly available Internal Revenue Service Form T-990 tax returns from disease-specific organizations. For SCD, we included 11 nonprofit organizations with at least 1 year of expenditures exceeding $500 000 during 2008 to 2017. Of the 110 Form T-990s, 9 were not available. For the missing forms, we imputed the mean expenses during the study period. We analyzed the Form T-990s for the 2 major CF organizations: the Cystic Fibrosis Foundation and Cystic Fibrosis Therapeutics (detailed expenditures in the eTable in the Supplement).

    We developed a comprehensive search strategy with a medical informaticist to identify publications as a measure of research productivity. We performed a PubMed search from January 1, 1940, to December 31, 2018, which provided an overview of the research output of the 2 diseases over time. Two independent reviewers (including one of us [J.J.S.]) audited the search strategy and evaluated the results for validity.

    We reviewed disease-specific US-based interventional trials on ClinicalTrials.gov from 2008 to 2018 using the search terms sickle cell and cystic fibrosis. Two independent reviewers (including one of us [J.J.S.]) audited the search results for validity. In addition, we divided the trials listed by funding source: (1) NIH and federal, (2) industry, and (3) other (foundation or university). We also reviewed the number of unique disease-specific FDA drug approvals and specific drug indications for each disease.

    Statistical Analysis

    We compared values between SCD and CF using an unpaired t test. Statistical significance was set at a 2-tailed P < .05. Statistical analysis was performed using Excel (Microsoft).

    Results

    Published estimates19-22 of approximately 90 000 individuals with SCD and approximately 30 000 individuals with CF from 2008 to 2018 were used (Table 1). The NIH funding per person with CF was greater than that for SCD (mean [SD], $2807 [$175] vs $812 [$147]; P < .001) (Table 2). The numbers of NIH career development awards for both diseases were similar (mean [SD], 16.6 [1.74] vs 16.7 [2.87]; P = .92) (Table 1). Philanthropic expenditures were significantly greater per person with CF compared with SCD (mean [SD], $7690 [$3974] vs $102 [$13.7]; P < .001).

    The number of PubMed publications per year was initially similar for the 2 diseases, but CF research output increased at a significantly quicker rate. During 2008 to 2018, annual CF publications remained greater than those of SCD (mean [SD] publications, 1594 [225] vs 926 [157]; P < .001) (Figure 1). Total interventional clinical trial listings on ClinicalTrials.gov for CF were greater than those for SCD from 2008 to 2018 (mean [SD] listings, 27.3 [6.9] vs 23.8 [6.3]; P = .22), but the difference was not statistically different. The SCD trials were more likely to be funded by NIH and federal funding (mean [SD], 5 [2.6] vs 1.9 [1.1]; P = .001) or foundation and university funding (mean [SD], 12.5 [6.1] vs 10.2 [2.9]; P = .27), but the difference for the latter was not statistically significant. The CF trials were significantly more likely to receive industry funding (mean [SD] trials, 15.6 [5.3] vs 6.8 [1.8]; P = .001) (Table 3).

    Disease-specific drug development also favored CF (4 vs 1 drug approvals) (Table 1). There were 6 disease-specific drugs for CF compared with 2 for SCD (Figure 1). Since 2012, the 3 novel disease-specific drugs that were approved for CF received 5 new indications. For SCD, only hydroxyurea received a new indication in 2017, and l-glutamine was initially approved for SCD the same year.

    Discussion

    Despite SCD being 3 times as prevalent as CF, both diseases received a similar amount of federal government research funding between 2008 and 2018. The funding disparity was markedly increased when factoring in disease-specific private foundation funding. The additional research support was associated with greater research productivity and pharmaceutical development for CF compared with SCD.

    Federal Disease-Specific Funding and Disease Burden

    The NIH allocates research funds in accordance with disease burden.18 Heart disease and cancer receive the largest amounts of funding because they are associated with significant morbidity and mortality for millions of people. Although SCD is 3 times as prevalent as CF, both diseases receive approximately equal NIH funding. It is challenging to calculate methods of disease burden, such as disability-adjusted life-years, for chronic genetic diseases. However, CF and SCD are associated with substantial health care–related costs, especially for hospital care, and have considerable effects on daily life.25-27 With the exception of recently developed CFTR modulator therapies, approximately 80% of the health care cost associated with each disease is spent on hospital care.25,27 The cost of health care for patients increases with age; thus, as more patients grow into adulthood, costs are expected to increase further.25

    Philanthropic Foundation Funding

    The size and revenue of medical charities generally reflect the disease burden. The American Heart Association and American Cancer Society are the 2 largest nonprofit health care organizations in the United States.28 However, when a disease relies heavily on foundation expenditures, disparities in funding can have a substantial effect on research productivity and clinical care. Our study found disparities in foundation funding between SCD and CF. The funding discrepancy was, to our knowledge, first reported in 1970 by Robert Scott,8,9 who framed SCD as a neglected public health crisis. The articles by Scott, along with the establishment of the National Association for Sickle Cell Disease in 1970, contributed to the passage of the National Sickle Cell Anemia Control Act in 1972 (Figure 2).29-31 This initiative increased federal funding and community-based screening for the disease. However, despite this public-private effort, NIH and foundation funding for SCD has remained low compared with CF.32 Fundraising capacity for private charitable organizations relies heavily on advocacy and donors who have the capacity to contribute. Even though sources of charitable funding are diverse, most of the SCD community is black.1 Despite black individuals donating a substantial portion of their income for philanthropy, there are many competing societal demands for charitable donations.28 In addition, there is historical distrust of the medical establishment among the black community, contributing to decreased funding and participation in medical research.33 The community affected by SCD may benefit from increased awareness and media exposure to increase advocacy to support federal and private investment in research.

    Research Productivity

    Measuring the association between research funding and productivity is complex and controversial. Although funding and grants can be easily measured, quantifying research productivity is challenging.34 Our data revealed that CF funding and research publications were consistently greater than those for SCD. The magnitude of funding disparity was substantially greater than the magnitude of measurable research disparity. Research publications were similar (Figure 1).

    Pharmaceutical Funding and Drug Development

    Recent breakthrough research and discoveries have been in biopharmaceuticals. Despite the slowing rate of federal government pharmaceutical funding, pharmaceutical funding from the private sector has been increasing, with an estimated $90 billion spent annually in research and development.35,36 In addition, there has been a renewed focus on drug development for rare diseases that affect fewer than 200 000 people. Since 2013, 60% of breakthrough therapies that have obtained FDA approval were designated as orphan drugs under the 1983 Orphan Drug Act.37

    Both CF and SCD are classified as rare diseases, and new products are eligible for orphan drug incentives; however, it is challenging to ascertain disease-specific investment by the pharmaceutical industry. Data from ClinicalTrials.gov showed that there have been more than twice as many industry-funded trials for CF compared with SCD. In addition, the Cystic Fibrosis Foundation’s venture philanthropy model has helped produce breakthrough therapies for CF.14-16 The unified Cystic Fibrosis Foundation allows for the investment of large sums in early-stage drug development, which has contributed to novel CFTR modulator therapies. The present analysis did not directly include payment in 2014 of $3.3 billion to the Cystic Fibrosis Foundation for the royalties from ivacaftor. This large lump sum has been reinvested for further research, drug development, and quality improvement efforts for persons with CF.38 Although this is an atypical 1-time occurrence, the magnitude of the transaction may have far-reaching effects and may be associated with increased disparity in private funding between these 2 diseases. The success of this venture philanthropy model can be seen in the increased Cystic Fibrosis Foundation funding beginning in 2015 and can support an additional $158 million dollars of annual expenditures at a spending rate of 4.8% (mean rate for endowment over $1 billion from 2000 to 2016).39

    In contrast, the few breakthroughs in SCD management occurred almost incidentally. In 1984, a patient with acute lymphoid leukemia and SCD underwent hematopoietic stem cell transplant, which also cured his SCD.40 The same year, hydroxyurea, once a chemotherapy agent, was found to increase fetal hemoglobin levels in SCD.41 However, hydroxyurea was not approved by the FDA until 1998 for the treatment of adults with severe SCD. A specific FDA indication for children was not obtained until 2017. The development of targeted therapies for CF within 25 years of discovering the genetic mechanism of the disease further accentuates the almost century-long drought in drug development for SCD.42 However, there were multiple advancements in SCD therapies in 2017. L-glutamine was the first disease-specific therapy developed for SCD to gain FDA approval.43 The same year, crizanlizumab, a humanized monoclonal antibody, demonstrated efficacy in reducing vasoocclusive crises, and the first case report of a patient undergoing successful lentiviral vector–mediated gene therapy for SCD was published.44,45

    Despite substantial advancements, CF and SCD therapies have notable shortcomings. Targeted therapies are effective for only a certain percentage of patients with CF and are not curative agents.46 Therapies have improved markers of disease activity, such as forced expiratory volume and reduced pulmonary exacerbations.14-16 Analogously, therapies for SCD have also improved fetal hemoglobin levels and reduced vasoocclusive crises.43,45,47,48 Although hematopoietic stem cell transplant is curative for SCD, the risk of treatment-related mortality, late adverse effects, and lack of eligible donors have limited uptake of this therapy.49-51 Going forward, CF and SCD may benefit from the renewed focus on the development of orphan drugs, precision medicine, and gene therapy52

    Access to Quality Comprehensive Care

    Novel disease-modifying therapies may be associated with improved survival for the population with CF, but the standard of the successful CF care model is comprehensive, multidisciplinary care obtained in specialized care centers. Multidisciplinary disease-specific comprehensive care centers have emerged to care for people with genetic diseases.53 The influence of the Cystic Fibrosis Foundation has involved research funding and the implementation of national quality-of-care standards the accredited comprehensive centers must uphold. There are more than 120 comprehensive care centers for CF in total, and 100 centers also provide adult care. In comparison, federal funding for 10 sickle cell centers ended in 2008; thus, there are no longer federally supported centers for comprehensive SCD care.53 Existing SCD comprehensive centers typically depend on institutional support because third-party reimbursement for clinical services is generally low; most individuals with SCD have Medicaid coverage, which is associated with decreased access to high-quality care and more emergency department use.54

    National patient registries for CF are used to evaluate adherence to guidelines, benchmark CF centers, and provide data for quality improvement efforts.55 For SCD, evidence-based guidelines exist, but the adaptation of best practices has been variable.56 For example, a previous study57 suggested that only 25% of eligible adults with SCD are prescribed hydroxyurea despite the drug’s proven efficacy since the early 1990s. The substantial improvement in life expectancy in patients with SCD and CF may be associated with the earlier and optimal application of supportive care and disease-modifying therapies. Most patients with CF and SCD in the United States now reach adulthood.58,59 Although childhood mortality related to SCD has steadily improved, the number of deaths from SCD among adults has been increasing.60

    Despite the differences in funding, the overall life expectancy of patients with SCD has increased at a faster rate than that of patients with CF during the past 2 decades (Figure 2). This finding may reflect greater disease severity of CF or a less representative sample for SCD because most recent survival studies23,61 for SCD have been limited to adults followed up at a single center of excellence. For example, a previous analysis62 demonstrated that the increased life expectancy of patients with CF observed in Canada compared with the US may be associated with insurance status in the US and access to lung transplants. This finding underscores the need for the communities involved with CF and SCD to develop an infrastructure to ensure access to optimal care for affected individuals.

    Race/Ethnicity and Stigma

    The role of race/ethnicity in the context of health care disparities in the US is well documented.63 Consideration of SCD as a black disease in the US has permeated the experience for patients since the first description in the Western medical literature.64 Even initial screening efforts for SCD were partially motivated by racial/ethnic undertones.65 CF has been recognized as a predominantly white disease; however, health care disparities associated with race/ethnicity also affect Hispanic individuals with CF. There is increased mortality among Hispanic patients with CF and relative underrepresentation in clinical trials.66,67 The interaction of black individuals with the health care system is associated with distrust given past ethical violations in the name of medical progress.68 This distrust between patient and practitioner can lead to conflict that results in suboptimal medical care and worsens patient medication adherence.69

    Stigma for people with SCD is most apparent when they are in the emergency department with severe pain and require compassionate, evidence-based care.70 In comparison, a measured decrease in lung function that requires airway clearance and antibiotics during a CF pulmonary exacerbation is not as stigmatizing as the report of severe pain that requires opiates during a vasoocclusive crisis. The recommended treatment for acute sickle cell pain involves medications associated with abuse, misuse, and addiction, which further challenges the clinical decision-making of practitioners. Not only are individuals with SCD already stigmatized as drug seeking, the nationwide focus on the opioid epidemic poses a new challenge for individuals in pain. Increasing disease awareness, educating practitioners, and developing coordinated care models can help mitigate stigma.71

    Recommendations

    A robust national organization linked with state and local chapters can pool funds to increase research funding, clinical trials, novel therapeutics, and develop interconnected comprehensive care centers. This approach has been successfully modeled by the Cystic Fibrosis Foundation,72 and patients with SCD may benefit from similar approaches. Current charitable SCD organizations are disjointed and have limited success with fundraising given reliance on small donations from the community affected by the disease. Robust financial support from established large foundations appears to be necessary to fund advocacy efforts and breakthrough research projects. Effective advocacy involves leveraging the changing media landscape to generate disease interest and develop corporate and community partnerships to boost funding.73

    We believe that the federal government should increase funding for SCD given the gap in private support and the association of funding with quality of life and survival. Federal legislative advocacy should also involve reestablishing federally funded comprehensive SCD treatment centers to complement existing support from the Health Resources and Services Administration for SCD Treatment Demonstration Regional Collaboratives.74 Research, education, and clinical care are shared missions of academic centers, and there appears to be opportunity for improvement in all 3 domains with regard to SCD. The more complex societal challenge involves overcoming mistrust and racism to empower and engage a community affected by the disease that has been historically disenfranchised.75 In addition, we propose partnerships among SCD practitioners, patient advocates, public health officials, and third-party payers to invest in improved comprehensive care for persons with SCD.

    Limitations

    This study has limitations. We cannot account for research funding by the NIH or other foundations that are not specific to SCD or CF. It is challenging to ascertain disease-specific investment by the pharmaceutical industry. This analysis also did not directly include the 1-time lump sum of $3.3 billion generated by the Cystic Fibrosis Foundation from royalties from the sale of ivacaftor.38 The shortcomings in using disease-specific bibliometrics, such as number of publications and citations, are that they generally do not capture the true value of breakthrough accomplishments and discoveries.

    Conclusions

    The findings show that disparities in funding between SCD and CF may be associated with decreased research productivity and novel drug development for SCD. Increased federal and foundation funding is needed for SCD and other diseases that disproportionately affect economically disadvantaged groups to address health care disparities.

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    Article Information

    Accepted for Publication: January 3, 2020.

    Published: March 27, 2020. doi:10.1001/jamanetworkopen.2020.1737

    Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2020 Farooq F et al. JAMA Network Open.

    Corresponding Author: John J. Strouse, MD, PhD, Division of Hematology, Duke University School of Medicine, DUMC 3939, Durham, NC 27710 (john.strouse@duke.edu).

    Author Contributions: Drs Farooq and Strouse had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Farooq, Mogayzel, Lanzkron, Haywood, Strouse.

    Acquisition, analysis, or interpretation of data: Farooq, Lanzkron, Haywood, Strouse.

    Drafting of the manuscript: Farooq, Haywood, Strouse.

    Critical revision of the manuscript for important intellectual content: Farooq, Mogayzel, Lanzkron, Strouse.

    Statistical analysis: Farooq.

    Obtained funding: Strouse.

    Administrative, technical, or material support: Strouse.

    Supervision: Mogayzel, Strouse.

    Conflict of Interest Disclosures: Dr Mogayzel reported receiving grant funding from Vertex Pharmaceuticals and being a member of the Cystic Fibrosis Foundation Board of Directors. Dr Lanzkron reported being a site principal investigator on research funded by Pfizer, Ironwood, and Global Blood Therapeutics. Dr Strouse reported being a consultant for Global Blood Therapeutics, serving as a site principal investigator on research funded by Takeda, and serving as treasurer of the Sickle Cell Adult Provider Network. No other disclosures were reported.

    Funding/Support: This study was supported by grant U1EMC27864 from the Health Resources and Service Administration (Dr Strouse).

    Role of the Funder/Sponsor: The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Meeting Presentation: Preliminary results from this analysis were presented in part at the American Society of Hematology 2018 Annual Meeting; December 3, 2018; San Diego, California.

    References
    1.
    Centers for Disease Control and Prevention.  Data & Statistics on Sickle Cell Disease. Centers for Disease Control and Prevention; 2017.
    2.
    Lin  JH, Collaco  JM, Paranjape  SM.  Cystic fibrosis in a Hispanic adolescent.  Pediatr Pulmonol. 2014;49(3):E40-E41. doi:10.1002/ppul.22758PubMedGoogle ScholarCrossref
    3.
    Spoonhower  KA, Davis  PB.  Epidemiology of cystic fibrosis.  Clin Chest Med. 2016;37(1):1-8. doi:10.1016/j.ccm.2015.10.002PubMedGoogle ScholarCrossref
    4.
    Herrick  JB.  Peculiar elongated and sickle-shaped red blood corpuscles in a case of severe anemia.  JAMA. 2014;312(10):1063. doi:10.1001/jama.2014.11011PubMedGoogle ScholarCrossref
    5.
    Pauling  L, Itano  HA, Singer  SJ, Wells  IC.  Sickle cell anemia a molecular disease.  Science. 1949;110(2865):543-548. doi:10.1126/science.110.2865.543PubMedGoogle ScholarCrossref
    6.
    Ingram  VM.  Abnormal human haemoglobins, I: the comparison of normal human and sickle-cell haemoglobins by fingerprinting.  Biochim Biophys Acta. 1958;28(3):539-545. doi:10.1016/0006-3002(58)90516-XPubMedGoogle ScholarCrossref
    7.
    Beutler  E.  The effect of methemoglobin formation in sickle cell disease.  J Clin Invest. 1961;40(10):1856-1871. doi:10.1172/JCI104410PubMedGoogle ScholarCrossref
    8.
    Scott  RB.  Health care priority and sickle cell anemia.  JAMA. 1970;214(4):731-734. doi:10.1001/jama.1970.03180040039008PubMedGoogle ScholarCrossref
    9.
    Scott  RB.  Sickle-cell anemia: high prevalence and low priority.  N Engl J Med. 1970;282(3):164-165. doi:10.1056/NEJM197001152820312PubMedGoogle ScholarCrossref
    10.
    Andersen  DH.  Cystic fibrosis of the pancreas and its relation to celiac disease: a clinical and pathologic study.  AJDC. 1938;56(2):344-399. doi:10.1001/archpedi.1938.01980140114013Google Scholar
    11.
    Kerem  B, Rommens  JM, Buchanan  JA,  et al.  Identification of the cystic fibrosis gene: genetic analysis.  Science. 1989;245(4922):1073-1080. doi:10.1126/science.2570460PubMedGoogle ScholarCrossref
    12.
    Riordan  JR, Rommens  JM, Kerem  B,  et al.  Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA.  Science. 1989;245(4922):1066-1073. doi:10.1126/science.2475911PubMedGoogle ScholarCrossref
    13.
    Rommens  JM, Iannuzzi  MC, Kerem  B,  et al.  Identification of the cystic fibrosis gene: chromosome walking and jumping.  Science. 1989;245(4922):1059-1065. doi:10.1126/science.2772657PubMedGoogle ScholarCrossref
    14.
    Ramsey  BW, Davies  J, McElvaney  NG,  et al; VX08-770-102 Study Group.  A CFTR potentiator in patients with cystic fibrosis and the G551D mutation.  N Engl J Med. 2011;365(18):1663-1672. doi:10.1056/NEJMoa1105185PubMedGoogle ScholarCrossref
    15.
    Wainwright  CE, Elborn  JS, Ramsey  BW,  et al; TRAFFIC Study Group; TRANSPORT Study Group.  Lumacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR.  N Engl J Med. 2015;373(3):220-231. doi:10.1056/NEJMoa1409547PubMedGoogle ScholarCrossref
    16.
    Taylor-Cousar  JL, Munck  A, McKone  EF,  et al.  Tezacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del.  N Engl J Med. 2017;377(21):2013-2023. doi:10.1056/NEJMoa1709846PubMedGoogle ScholarCrossref
    17.
    Moses  H  III, Matheson  DH, Cairns-Smith  S, George  BP, Palisch  C, Dorsey  ER.  The anatomy of medical research: US and international comparisons.  JAMA. 2015;313(2):174-189. doi:10.1001/jama.2014.15939PubMedGoogle ScholarCrossref
    18.
    National Institutes of Health.  Report on NIH Funding vs. Global Burden of Disease. National Institutes of Health; 2018.
    19.
    Hassell  KL.  Population estimates of sickle cell disease in the U.S.  Am J Prev Med. 2010;38(4)(suppl):S512-S521. doi:10.1016/j.amepre.2009.12.022PubMedGoogle ScholarCrossref
    20.
    Cystic Fibrosis Foundation.  Patient Registry Annual: Data Report. Cystic Fibrosis Foundation; 2017.
    21.
    Feuchtbaum  L, Carter  J, Dowray  S, Currier  RJ, Lorey  F.  Birth prevalence of disorders detectable through newborn screening by race/ethnicity.  Genet Med. 2012;14(11):937-945. doi:10.1038/gim.2012.76PubMedGoogle ScholarCrossref
    22.
    Lorey  FW, Arnopp  J, Cunningham  GC.  Distribution of hemoglobinopathy variants by ethnicity in a multiethnic state.  Genet Epidemiol. 1996;13(5):501-512. doi:10.1002/(SICI)1098-2272(1996)13:5<501::AID-GEPI6>3.0.CO;2-4PubMedGoogle ScholarCrossref
    23.
    Elmariah  H, Garrett  ME, De Castro  LM,  et al.  Factors associated with survival in a contemporary adult sickle cell disease cohort.  Am J Hematol. 2014;89(5):530-535. doi:10.1002/ajh.23683PubMedGoogle ScholarCrossref
    24.
    National Institutes of Health.  Estimates of Funding for Various Research, Condition, and Disease Categories (RCDC). National Institutes of Health; 2017.
    25.
    Kauf  TL, Coates  TD, Huazhi  L, Mody-Patel  N, Hartzema  AG.  The cost of health care for children and adults with sickle cell disease.  Am J Hematol. 2009;84(6):323-327. doi:10.1002/ajh.21408PubMedGoogle ScholarCrossref
    26.
    van Gool  K, Norman  R, Delatycki  MB, Hall  J, Massie  J.  Understanding the costs of care for cystic fibrosis: an analysis by age and health state.  Value Health. 2013;16(2):345-355. doi:10.1016/j.jval.2012.12.003PubMedGoogle ScholarCrossref
    27.
    Hassan  M, Bonafede  MM, Limone  BL, Hodgkins  P, Sawicki  GS.  The burden of cystic fibrosis in the Medicaid population.  Clinicoecon Outcomes Res. 2018;10:423-431. doi:10.2147/CEOR.S162021PubMedGoogle ScholarCrossref
    28.
    US Trust; Indiana University Lilly Family School of Philanthropy. High net worth philanthropy: charitable practices and preferences of wealthy households. October 2016. Accessed February 22, 2020. https://scholarworks.iupui.edu/bitstream/handle/1805/11234/high-net-worth_oct_2017-1.pdf?sequence=4&isAllowed=y
    29.
    Wailoo  K.  Sickle cell disease—a history of progress and peril.  N Engl J Med. 2017;376(9):805-807. doi:10.1056/NEJMp1700101PubMedGoogle ScholarCrossref
    30.
    Elborn  JS.  Personalised medicine for cystic fibrosis: treating the basic defect.  Eur Respir Rev. 2013;22(127):3-5. doi:10.1183/09059180.00008112PubMedGoogle ScholarCrossref
    31.
    National Sickle Cell Anemia Control Act, Pub L No. 92-2941972.
    32.
    Benson  JM, Therrell  BL  Jr.  History and current status of newborn screening for hemoglobinopathies.  Semin Perinatol. 2010;34(2):134-144. doi:10.1053/j.semperi.2009.12.006PubMedGoogle ScholarCrossref
    33.
    Scharff  DP, Mathews  KJ, Jackson  P, Hoffsuemmer  J, Martin  E, Edwards  D.  More than Tuskegee: understanding mistrust about research participation.  J Health Care Poor Underserved. 2010;21(3):879-897. doi:10.1353/hpu.0.0323PubMedGoogle ScholarCrossref
    34.
    Ioannidis  JP, Klavans  R, Boyack  KW.  Multiple citation indicators and their composite across scientific disciplines.  PLoS Biol. 2016;14(7):e1002501. doi:10.1371/journal.pbio.1002501PubMedGoogle Scholar
    35.
    Dorsey  ER, de Roulet  J, Thompson  JP,  et al.  Funding of US biomedical research, 2003-2008.  JAMA. 2010;303(2):137-143. doi:10.1001/jama.2009.1987PubMedGoogle ScholarCrossref
    36.
    PhRMA. Biopharmaceutical Research Industry Profile and Toolkit. PhRMA; 2018.
    37.
    Lanthier  M.  Insights Into Rare Disease Drug Approval: Trends and Recent Developments. US Food and Drug Administration; 2017.
    38.
    Walker  J, Rockoff  JD. Cystic Fibrosis Foundation sells drugs rights for $3.3 billion: the biggest royalty purchase ever reflects group’s share of Kalydeco sales. Wall Street Journal. November 19, 2014. Accessed February 24, 2020. https://www.wsj.com/articles/cystic-fibrosis-foundation-sells-drugs-rights-for-3-3-billion-1416414300
    39.
    Seltzer  R. Endowment returns slow: survey offers peek at spending. Inside Higher Ed. January 31, 2019. Accessed February 22, 2020. https://www.insidehighered.com/news/2019/01/31/college-endowments-returned-82-percent-2018-annual-survey-adds-some-insight-how
    40.
    Johnson  FL, Look  AT, Gockerman  J, Ruggiero  MR, Dalla-Pozza  L, Billings  FT  III.  Bone-marrow transplantation in a patient with sickle-cell anemia.  N Engl J Med. 1984;311(12):780-783. doi:10.1056/NEJM198409203111207PubMedGoogle ScholarCrossref
    41.
    Platt  OS, Orkin  SH, Dover  G, Beardsley  GP, Miller  B, Nathan  DG.  Hydroxyurea enhances fetal hemoglobin production in sickle cell anemia.  J Clin Invest. 1984;74(2):652-656. doi:10.1172/JCI111464PubMedGoogle ScholarCrossref
    42.
    O’Reilly  R, Elphick  HE.  Development, clinical utility, and place of ivacaftor in the treatment of cystic fibrosis.  Drug Des Dev Ther. 2013;7:929-937.PubMedGoogle Scholar
    43.
    Niihara  Y, Koh  HA, Tran  L,  et al.  A phase 3 study of l-glutamine therapy for sickle cell anemia and sickle β0-thalassemia.  Blood. 2014;124(21):86-86. doi:10.1182/blood.V124.21.86.86Google ScholarCrossref
    44.
    Ribeil  JA, Hacein-Bey-Abina  S, Payen  E,  et al.  Gene therapy in a patient with sickle cell disease.  N Engl J Med. 2017;376(9):848-855. doi:10.1056/NEJMoa1609677PubMedGoogle ScholarCrossref
    45.
    Ataga  KI, Kutlar  A, Kanter  J,  et al.  Crizanlizumab for the prevention of pain crises in sickle cell disease.  N Engl J Med. 2017;376(5):429-439. doi:10.1056/NEJMoa1611770PubMedGoogle ScholarCrossref
    46.
    Mall  MA, Mayer-Hamblett  N, Rowe  SM.  Cystic fibrosis: emergence of highly effective targeted therapeutics and potential clinical implications.  Am J Respir Crit Care Med. 2019. doi:10.1164/rccm.201910-1943SOPubMedGoogle Scholar
    47.
    Niihara  Y, Miller  ST, Kanter  J,  et al; Investigators of the Phase 3 Trial of l-Glutamine in Sickle Cell Disease.  A phase 3 trial of l-glutamine in sickle cell disease.  N Engl J Med. 2018;379(3):226-235. doi:10.1056/NEJMoa1715971PubMedGoogle ScholarCrossref
    48.
    Heeney  MM, Hoppe  CC, Abboud  MR,  et al; DOVE Investigators.  A multinational trial of prasugrel for sickle cell vaso-occlusive events.  N Engl J Med. 2016;374(7):625-635. doi:10.1056/NEJMoa1512021PubMedGoogle ScholarCrossref
    49.
    Arnold  SD, Brazauskas  R, He  N,  et al.  Clinical risks and healthcare utilization of hematopoietic cell transplantation for sickle cell disease in the USA using merged databases.  Haematologica. 2017;102(11):1823-1832. doi:10.3324/haematol.2017.169581PubMedGoogle ScholarCrossref
    50.
    Khemani  K, Ross  D, Sinha  C, Haight  A, Bakshi  N, Krishnamurti  L.  Experiences and decision making in hematopoietic stem cell transplant in sickle cell disease: patients’ and caregivers’ perspectives.  Biol Blood Marrow Transplant. 2018;24(5):1041-1048. doi:10.1016/j.bbmt.2017.11.018PubMedGoogle ScholarCrossref
    51.
    Shenoy  S, Angelucci  E, Arnold  SD,  et al.  Current results and future research priorities in late effects after hematopoietic stem cell transplantation for children with sickle cell disease and thalassemia: a consensus statement from the Second Pediatric Blood and Marrow Transplant Consortium International Conference on Late Effects After Pediatric Hematopoietic Stem Cell Transplantation.  Biol Blood Marrow Transplant. 2017;23(4):552-561. doi:10.1016/j.bbmt.2017.01.009PubMedGoogle ScholarCrossref
    52.
    Burney  TJ, Davies  JC.  Gene therapy for the treatment of cystic fibrosis.  Appl Clin Genet. 2012;5:29-36.PubMedGoogle Scholar
    53.
    Grosse  SD, Schechter  MS, Kulkarni  R, Lloyd-Puryear  MA, Strickland  B, Trevathan  E.  Models of comprehensive multidisciplinary care for individuals in the United States with genetic disorders.  Pediatrics. 2009;123(1):407-412. doi:10.1542/peds.2007-2875PubMedGoogle ScholarCrossref
    54.
    Robinson  MR, Daniel  LC, O’Hara  EA, Szabo  MM, Barakat  LP.  Insurance status as a sociodemographic risk factor for functional outcomes and health-related quality of life among youth with sickle cell disease.  J Pediatr Hematol Oncol. 2014;36(1):51-56. doi:10.1097/MPH.0000000000000013PubMedGoogle ScholarCrossref
    55.
    Marshall  BC, Nelson  EC.  Accelerating implementation of biomedical research advances: critical elements of a successful 10 year Cystic Fibrosis Foundation healthcare delivery improvement initiative.  BMJ Qual Saf. 2014;23(suppl 1):i95-i103. doi:10.1136/bmjqs-2013-002790PubMedGoogle ScholarCrossref
    56.
    National Heart, Lung, and Blood Institute.  Evidence-Based Management of Sickle Cell Disease: Expert Panel Report, 2014. National Heart, Lung, and Blood Institute; 2014.
    57.
    Stettler  N, McKiernan  CM, Melin  CQ, Adejoro  OO, Walczak  NB.  Proportion of adults with sickle cell anemia and pain crises receiving hydroxyurea.  JAMA. 2015;313(16):1671-1672. doi:10.1001/jama.2015.3075PubMedGoogle ScholarCrossref
    58.
    Quinn  CT, Rogers  ZR, McCavit  TL, Buchanan  GR.  Improved survival of children and adolescents with sickle cell disease.  Blood. 2010;115(17):3447-3452. doi:10.1182/blood-2009-07-233700PubMedGoogle ScholarCrossref
    59.
    Konstan  MW, VanDevanter  DR, Sawicki  GS,  et al.  Association of high-dose ibuprofen use, lung function decline, and long-term survival in children with cystic fibrosis.  Ann Am Thorac Soc. 2018;15(4):485-493. doi:10.1513/AnnalsATS.201706-486OCPubMedGoogle ScholarCrossref
    60.
    Lanzkron  S, Carroll  CP, Haywood  C  Jr.  Mortality rates and age at death from sickle cell disease: U.S., 1979-2005.  Public Health Rep. 2013;128(2):110-116. doi:10.1177/003335491312800206PubMedGoogle ScholarCrossref
    61.
    Wierenga  KJJ, Hambleton  IR, Lewis  NA; Sickle Cell Unit.  Survival estimates for patients with homozygous sickle-cell disease in Jamaica: a clinic-based population study.  Lancet. 2001;357(9257):680-683. doi:10.1016/S0140-6736(00)04132-5PubMedGoogle ScholarCrossref
    62.
    Stephenson  AL, Sykes  J, Stanojevic  S,  et al.  Survival comparison of patients with cystic fibrosis in Canada and the United States: a population-based cohort study.  Ann Intern Med. 2017;166(8):537-546. doi:10.7326/M16-0858PubMedGoogle ScholarCrossref
    63.
    Smedley  BD, Stith  AY, Nelson  AR, eds.  Institute of Medicine Committee on Understanding Eliminating Racial Ethnic Disparities in Health Care. Unequal Treatment: Confronting Racial and Ethnic Disparities in Health Care. National Academies Press; 2002.
    64.
     Sickle cell anemia, a race specific disease.  JAMA. 1947;133(1):33-34. doi:10.1001/jama.1947.02880010035011Google Scholar
    65.
    Wailoo  K, Pemberton  S.  The Troubled Dream of Genetic Medicine: Ethnicity and Innovation in Tay-Sachs, Cystic Fibrosis, and Sickle Cell Disease. Johns Hopkins University Press; 2006.
    66.
    McGarry  ME, McColley  SA.  Minorities are underrepresented in clinical trials of pharmaceutical agents for cystic fibrosis.  Ann Am Thorac Soc. 2016;13(10):1721-1725. doi:10.1513/AnnalsATS.201603-192BCPubMedGoogle Scholar
    67.
    Buu  MC, Sanders  LM, Mayo  JA, Milla  CE, Wise  PH.  Assessing differences in mortality rates and risk factors between Hispanic and non-Hispanic patients with cystic fibrosis in California.  Chest. 2016;149(2):380-389. doi:10.1378/chest.14-2189PubMedGoogle ScholarCrossref
    68.
    Webb Hooper  M, Mitchell  C, Marshall  VJ,  et al.  Understanding multilevel factors related to urban community trust in healthcare and research.  Int J Environ Res Public Health. 2019;16(18):E3280. doi:10.3390/ijerph16183280PubMedGoogle Scholar
    69.
    Haywood  C  Jr, Lanzkron  S, Bediako  S,  et al; IMPORT Investigators.  Perceived discrimination, patient trust, and adherence to medical recommendations among persons with sickle cell disease.  J Gen Intern Med. 2014;29(12):1657-1662. doi:10.1007/s11606-014-2986-7PubMedGoogle ScholarCrossref
    70.
    Sinha  CB, Bakshi  N, Ross  D, Krishnamurti  L.  Management of chronic pain in adults living with sickle cell disease in the era of the opioid epidemic: a qualitative study.  JAMA Netw Open. 2019;2(5):e194410. doi:10.1001/jamanetworkopen.2019.4410PubMedGoogle Scholar
    71.
    Bulgin  D, Tanabe  P, Jenerette  C.  Stigma of sickle cell disease: a systematic review.  Issues Ment Health Nurs. 2018;39(8):675-686. doi:10.1080/01612840.2018.1443530PubMedGoogle ScholarCrossref
    72.
    Cystic Fibrosis Foundation. Annual report 2018. Accessed February 21, 2020. https://www.cff.org/About-Us/Assets/2018-Annual-Report.pdf
    73.
    Furlong  P, Bridges  JF, Charnas  L,  et al.  How a patient advocacy group developed the first proposed draft guidance document for industry for submission to the US Food and Drug Administration.  Orphanet J Rare Dis. 2015;10:82. doi:10.1186/s13023-015-0281-2PubMedGoogle ScholarCrossref
    74.
    Health Resources and Services Administration. Sickle Cell Disease Treatment Demonstration Regional Collaboratives Program. Accessed February 21, 2020. https://www.hrsa.gov/grants/find-funding/hrsa-17-078
    75.
    Bleich  SN, Findling  MG, Casey  LS,  et al.  Discrimination in the United States: experiences of black Americans.  Health Serv Res. 2019;54(suppl 2):1399-1408. doi:10.1111/1475-6773.13220PubMedGoogle ScholarCrossref
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