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A Protected Class, An Unprotected Condition, and A Biomarker – A Method/Formula for Increased Diversity in Clinical Trials for the African American Subject with Benign Ethnic Neutropenia (BEN)

Published online by Cambridge University Press:  28 June 2023

Regina Ponder
Regina Ponder*
Affiliation:
National Coalition of 100 Black Women, Inc., Phoenix Metropolitan Chapter, Phoenix, AZ, USA
*
Email: researcher.ejd@gmail.com
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Abstract

Expanding on previous industry guidance relative to increased clinical trial diversity, while honing more exacting treatments and better ways to fight diseases that have often disproportionately impacted people of color, is a topic being discussed by multidisciplinary public health experts across the nation.

This writing draws attention to the African American demographic, which is continually subject to health care disparities. Any glimpses of knowledge or medical discovery that could potentially help to redress harm or reinforce a weakened familial-cultural infrastructure should be emphasized for sanative restoration of the impacted communities. The focus of this writing is the African American cohort and its nexus to Benign Ethnic Neutropenia as the diverse target population of discussion, hoping to convey a harmonized approach in the examination of (1) the African American Benign Ethnic Neutropenia cohort within the context of basic scientific understanding, (2) the interplay of applicable governing regulatory protections, and (3) increased clinical trial participation to enlarge the pathway for increased diversity in clinical trials.

Keywords

Benign Ethnic NeutropeniaClinical Trial DiversityAfrican-AmericansHuman Subject Protections

Information

Type
Articles
Information
American Journal of Law & Medicine , Volume 49 , Issue 1 , March 2023 , pp. 41 - 58
Copyright
© 2023 The Author(s)

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References

1 FDA Takes Important Steps to Increase Racial and Ethnic Diversity in Clinical Trials, U.S. Food & Drug Admin. (Apr. 13, 2022), https://www.fda.gov/news-events/press-announcements/fda-takes-important-steps-increase-racial-and-ethnic-diversity-clinical-trials [https://perma.cc/H35E-D7FC].

2 To view the comments submitted during the comment period, which concluded on June 12, 2022, see Diversity Plans to Improve Enrollment of Participants from Underrepresented Racial and Ethnic Populations in Clinical Trials; Draft Guidance for Industry; Availability, https://www.regulations.gov/docket/FDA-2021-D-0789/comments [https://perma.cc/8PAM-62GT].

3 Id.

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6 See Hughes, supra note 4.

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8 Note that in this writing, that the terms “African American,” “African descent,” and “African Ancestry,” as population descriptors, allude to the same race of individuals and are being used interchangeably unless otherwise contextually clarified.

9 Jan Palmblad & Petter Höglund, Ethnic benign neutropenia: A phenomenon finds an explanation, 65 Pediatric Blood & Cancer 12 (2018).

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12 To date, reporting sources for African American participation in trials have varied with some reporting rates as low as five percent. See Patrick Boyle, Clinical trials seek to fix their lack of racial mix, AAMCNews (Aug. 20, 2021), https://www.aamc.org/news-insights/clinical-trials-seek-fix-their-lack-racial-mix [https://perma.cc/8KUV-3KVZ].

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15 Id. at 42.

16 Id. at 44.

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18 Id.

19 Id.

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21 Id.

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29 Id.

30 See supra note 8.

31 Meghan Droste, What Are Protected Classes?, Subscript L. (June 22, 2020), https://subscriptlaw.com/protected-classes/ [https://perma.cc/AV8W-9FH8].

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34 Longley, supra note 32.

35 President Andrew Jackson, Veto Message on Civil Rights Legislation (Mar. 27, 1866).

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37 Robert J. Kaczorowski, Enforcement Provisions of the Civil Rights Act of 1866: A Legislative History in Light of Runyon v. McCrary, The Review Essay and Comments: Reconstructing Reconstruction, 98 Yale L. J. 565, 567 (1988).

38 Id. at 567 – 71.

39 Robert Longley, The Civil Rights Act of 1866, History and Impact, Thought Co. (Mar. 1, 2021), https://www.thoughtco.com/civil-rights-act-of-1866-4164345 [https://perma.cc/9JR7-6G7V].

40 Id.; 42 U.S.C. § 2000e et seq.

41 45 C.F.R. § 46.116 (2023).

42 OHRP, Nat’l Cancer Institute (last visited Apr. 4, 2023), https://www.cancer.gov/publications/dictionaries/cancer-terms/def/ohrp. [https://perma.cc/79Z7-3QLX].

43 21 C.F.R. § 56.111(a)(3) (2023).

44 21 C.F.R. § 56.111(b) (2023).

45 See generally 21 C.F.R. § 1.1.

46 21 C.F.R. § 312.87.

47 21 C.F.R. § 312.60 (2023); 21 C.F.R. § 812.110 (2023).

48 See Ananyo Choudhury et al., High-Depth African Genomes Inform Human Migration and Health, 586 Nature, 741–748 (2020).

49 Neil Munshi, How Unlocking the Secrets of African DNA Can Unlock the World, Fin. Times Mag. (Mar. 4, 2020), https://www.ft.com/content/eed0555c-5e2b-11ea-b0ab-339c2307bcd4 [https://perma.cc/7EXP-X924].

50 Katarzyna Bryc et al., Genome-Wide Patterns of Population Structure and Admixture in West Africans and African Americans, 107(2) PNAS 786-791 (2009).

51 Ctrs. for Disease & Control Prevention, Waived Tests, (Sept. 3, 2021) https://www.cdc.gov/labquality/waived-tests.html [https://perma.cc/8UZD-64WW]; U.S. Food & Drug Admin., Clinical Laboratory Improvement Amendments(CLIA) (Sept. 13, 2021), https://www.fda.gov/medical-devices/ivd-regulatory-assistance/clinical-laboratory-improvement-amendments-clia [https://perma.cc/27TY-W4RW] (“The Clinical Laboratory Improvement Amendments (CLIA) regulate laboratory testing and require clinical laboratories to be certified by the Center for Medicare and Medicaid Services (CMS) before they can accept human samples for diagnostic testing. Laboratories can obtain multiple types of CLIA certificates, based on the kinds of diagnostic tests they conduct. Three federal agencies are responsible for CLIA: The Food and Drug Administration (FDA), the Center for Medicaid Services (CMS), and the Centers for Disease Control and Prevention (CDC)”).

52 Matthew M. Hsieh, et al, Neutrophil Count in African Americans: Lowering the Target Cutoff to Initiate or Resume Chemotherapy? 28 J. Clinical Oncology 1633, 1637 (Apr. 1, 2010).

53 Suheil Albert Atallah-Yunes et al., Benign Ethnic Neutropenia, 37 Blood Rev. 1 (2019).

54 Id. at 10.

55 Id. at 1.

56 Id.

57 Naama Rappoport et al., The Duffy Antigen Receptor for Chemokines, ACKR1,– ‘Jeanne DARC’ of Benign Neutropenia,184 Brit, J. of Haematology 497, 497 (2018).

58 Id.

59 Ebenezer Oloyede et al., Benign Ethnic Neutropenia: An Analysis of Prevalence, Timing and Identification Accuracy in Two Large Inner-City NHS Hospitals, 21 BMC Psych. 502 at 1 (2021).

60 Theresa B. Haddy at al., Benign Ethnic Neutropenia: What is a Normal Absolute Neutrophil Count? 133(1) J. Lab. Clin. Med. 15, 15 (1999).

61 Leigh Macmillan, Gene Variant Linked to Unnecessary Bone Marrow Biopsies in African Americans, Van. U. Med. Ctr. Rep‥ June 28, 2021, https://news.vumc.org/2021/06/28/gene-variant-unnecessary-bone-marrow-biopsies-african-americans/.

62 Id.

63 Id.

64 Id.

65 See, e.g., Sophie E. Leggea et al., The Duffy-Null Genotype and Risk of Infection, 29(20) Hum. Molecular. Genetics. 3341 (2020) (“Duffy-null (CC) genotype at rs2814778, in the Atypical Chemokine Receptor 1 (ACKR1) gene, which has been robustly associated with reduced neutrophil counts in individuals of African ancestry and is considered to be the cause of BEN … It confers an evolutionary advantage by protecting against the malaria parasite Plasmodium vivax infection, and thus it is highly prevalent in geographical areas previously endemic to malaria, such as sub-Saharan Africa … It has a prevalence of approximately 80% in Black African/Caribbean populations in the UK, approximately 65% prevalence in African Americans, and is very rare in individuals of European ancestry.”); see also Macmillan, supra note 61.

66 Macmillan, supra note 61.

67 Atallah-Yunes, supra note 53; see also Lauren E. Merz & Maureen Achebe, When Non-Whiteness Becomes a Condition, 137(1) J. of Blood 13, 13 (2021).

68 For more information on the CHIPS and Science Act, and its effects, see FACT SHEET: CHIPS and Science Act will Lower Costs, Create Jobs, Strengthen Supply Chains, whitehouse.gov (Aug. 9, 2022), https://www.whitehouse.gov/briefing-room/statements-releases/2022/08/09/fact-sheet-chips-and-science-act-will-lower-costs-create-jobs-strengthen-supply-chains-and-counter-china/ [https://perma.cc/G648-U5ZE].

69 Trevor Sutton et al., The CHIPS and Science Act Will Invest in US Innovation and Create Jobs, Ctr. For Am. Progress (July 29, 2022), https://www.americanprogress.org/article/the-chips-and-science-act-will-invest-in-u-s-innovation-and-create-jobs/ [https://perma.cc/5NJX-RYRL].

70 Rahul Lakhotia et al., Natural History of Benign Ethnic Neutropenia in Individuals of African Ancestry, 77 Blood Cells, Molecules & Diseases 12, 15 (2019).

71 Merz & Achebe, supra note 67.

72 For an in-depth dive into the presmises of the National Research Act, see Research Implications, cdc.gov (April 22, 2021), https://www.cdc.gov/tuskegee/after.htm#print [https://perma.cc/MDS5-L6WF].

73 E.g., Todd W. Rice, The Historical, Ethical, and Legal Background of Human-Subjects Research, 53(10) Respiratory Care 1325, 1325 (2008).

74 See id.

75 See Committee on Revisions to the Common Rule for the Protection of human Subjects in Research in the Behavioral and Social Sciences, Proposed Revisions to the Common Rule for the Protection of Human Subjects in the Behavioral and Social Sciences 149 (Appendix A: Federal Policy for the Protection of Human Subjects (“Common Rule”)) (2014).

76 45 C.F.R § 46.109 (2022).

77 Id. at § 46.116h(3)).

78 Arun Bhatt, Evolution of Clinical Research: A History Before and Beyond James Lind, 1(1) Perspectives in Clinical Rsch. 6, 9 (2010).

79 Id.

80 See, e.g., Hilary Marston, FDA Takes Steps to Further Harmonize Clinical Research Regulations with HHS Common Rule, FDA (Oct. 6, 2022), https://www.fda.gov/news-events/fda-voices/fda-takes-steps-further-harmonize-clinical-research-regulations-hhs-common-rule [https://perma.cc/7ZEA-2NWE]

81 42 C.F.R § 11.10(b)(21).

82 45 C.F.R. § 46.102(i).

83 Off. for Hum. Rsrch Protections, Clinical Trial Websites: When is IRB Review Required and What Should IRB Consider with Reviewing? (Sept. 20, 2005), https://www.hhs.gov/ohrp/regulations-and-policy/guidance/clinical-trial-websites/index.html [https://perma.cc/EF99-FE85].

84 U.S. Food & Drug Admin., Collection of Race and Ethnicity Data in Clinical Trials (Oct. 2016), https://www.fda.gov/regulatory-information/search-fda-guidance-documents/collection-race-and-ethnicity-data-clinical-trials [https://perma.cc/PU6M-CVJT].

85 U.S. Food & Drug Admin., Public Workshop: Evaluating Inclusion and Exclusion Criteria in Clinical Trials, Workshop Report (April 16, 2018), https://www.fda.gov/media/134754/download.

86 Id. Eligibility criteria are a critical component of clinical trials, as they define the patient population under investigation.

87 Id; see also Table Three, infra.

88 Id.

89 Major Dan, March 1, 1790: The First Census (Census Shmensus), History and Headlines (Mar. 1, 2018), https://www.historyandheadlines.com/march-1-1790-first-us-census-census-shmensus/ [https://perma.cc/CN7B-HDW6].

90 See, e.g. Deyrup & Graves, supra note 23.

91 See Table One, infra. The Census can serve as a determinant for state and federal research needs, as well as for House representation needs: an imbalanced census creates a bias in policies and funding of state representation, which could impact health disparities. Additionally, ethnicities that do not have the traditional Eurocentric physical appearances of the White race in general, but categorically claim White status under the Census, have benefited from the Census’s structure. Consider George Shisham, a police officer of Lebanese-Syrian and Arab ancestry who worked as a police officer in 1909 in Venice, California: the judge presiding over Shisham’s citizenship case handed down a precedential decision that provided that people of Lebanese and Syrian descent were “White” for purposes of the Census and, ultimately, for citizenship purposes. Dept. of Justice Affirms in 1909 Whether Syrians, Turks, and Arabs are of White or Yellow Race, Arab American Historical Foundation (2011), https://www.arabamericanhistory.org/archives/dept-of-justice-affirms-arab-race-in-1909/#:~:text=George%20Shishim%20won%20his%20case%20with%20the%20Federal,the%20legal%20fight%20for%20Shishim%E2%80%99s%20eligibility%20to%20citizenship [https://perma.cc/D2E8-5HDA].

92 See Dan, supra note 98.

93 Dept. of Health, Education, & Welfare, The Belmont Report (April 18, 1979), https://www.hhs.gov/ohrp/regulations-and-policy/belmont-report/index.html [https://perma.cc/FL32-K5RV].

94 See Sarah L. Van Dreist et al., Association Between a Common, Benign Genotype and Unnecessary Bone Marrow Biopsies Among African American Patients, 181 JAMA Internal Med. 1100, 1100-05 (2021).

95 See Title 42 Part 11:10(b)(21), supra note 73.

96 Number of Veterans in the United States in 2019 By Race and Hispanic Origin, Statista (Sept. 2020), https://www.statista.com/statistics/616753/us-veterans-by-race-and-hispanic-origin/ [https://perma.cc/Z89H-K8YQ].

97 Id.

98 Off. of Health Equity, U.S. Dept of Veterans Affairs, Racial and Ethnic Minority Veterans (last updated July 9, 2020), https://www.va.gov/HEALTHEQUITY/Race_Ethnicity.asp [https://perma.cc/HN6L-WWSR].

99 Id.

100 Id.

101 Brandon E. Turner et al., Race/Ethnicity Reporting and Representation in US Clinical Trials: A Cohort Study, 11 The Lancet Regional Health – Americas 100252 (2022).

102 Id.

103 National Human Genome Research Institute, Genetic Discrimination, NIH (last updated: January 6, 2022), https://www.genome.gov/about-genomics/policy-issues/Genetic-Discrimination [https://perma.cc/CH5K-BGTM].

104 H.R. 913, 116th Cong. (2019-2020).

105 Id.; see also Sara Karlovitch, Clinical Treatment Act Aims to Improve Survival, Close Racial Health Care Gap, Targeted Oncology (June 28, 2021), https://www.targetedonc.com/view/clinical-treatment-act-aims-to-improve-survival-close-racial-health-care-gap [https://perma.cc/UK22-FNY8].

106 U.S. Dep’t of Health and Hum. Services, Common Terminology Criteria for Adverse Events (CTCAE), cancer.gov (Nov. 27, 2017), https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_5x7.pdf.

107 Atallah-Yunes, supra note 53.

108 21 C.F.R. § 312.53 (c) (1); 21 C.F.R. Part 803.

109 Ethan Basch et al.,Development of the National Cancer Institute’s patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE), J. Nat’l Cancer Inst. (Sep. 29, 2014).

110 Atallah-Yunes, supra note 53.

111 Matthew M. Hsieh et al.,Neutrophil count in African Americans: lowering the target cutoff to initiate or resume chemotherapy?, J. Clin Oncol. (2010).

112 Id.

113 Id.

114 Marie E. Vastola et al. Laboratory Eligibility Criteria as Potential Barriers to Participation by Black Men in Prostate Cancer Clinical Trials, 4 JAMA Oncol. 413, 413-14 (2018).

115 Atallah-Yunes, supra note 53.

116 Checklist to Understanding Biomarker Testing, Triage Cancer (last updated Nov. 2022), https://triagecancer.org/quick-guides/biomarker-testing. [https://perma.cc/A4DE-KBB5].

117 FDA-NIH Biomarker Working Group, BEST (Biomarkers, EndpointS, and other Tools) Resource 45 (2021).

118 Id.

119 Susceptibility biomarkers and risk biomarkers are that indicate “the potential for developing a disease or medical condition in an individual who does not currently have a clinically apparent disease or a medical condition.” Id. at 33.

120 Diagnostic biomarkers are biomarkers “used to detect or confirm the presence of a disease or condition of interest or to identify individuals with a subtype of the disease.” Id. at 5.

121 Monitoring biomarkers are biomarkers “measured repeatedly for assessing status of a disease or medical condition or for evidence of exposure to (or effect of) a medical product or an environmental agent.” Id. at 9.

122 Prognostic biomarkers are biomarkers “used to identify the likelihood of a clinical event, disease recurrence, or progression in patients who have the disease or medical condition of interest.” Id. at 23.

123 Predictive biomarkers are biomarkers “used to identify individuals who are more likely than similar individuals without the biomarker to experience a favorable or unfavorable effect from exposure to a medical product or an environmental agent.” Id. at 19.

124 Response biomarkers are biomarkers “used to show that a biological response, potentially beneficial or harmful, has occurred in an individual who has been exposed to a medical product or an environmental agent.” Id. at 15.

125 Safety biomarkers are biomarkers “measured before or after exposure to a medical product or an environmental agent to indicate the likelihood, presence, or extent of toxicity as an adverse effect.” Id. at 29.

126 Dictionary of Cancer Terms – Biomarker, The Nat’l Cancer Institute at the Nat’l Institutes of Health, https://www.cancer.gov/publications/dictionaries/cancer-terms/def/biomarker [https://perma.cc/2MZY-B6CW].

127 Id.

128 Human Subjects Research, National Human Genome Research Project (last updated Sept. 30, 2019), https://www.genome.gov/about-genomics/policy-issues/Human-Subjects-Research-in-Genomics [https://perma.cc/M5NG-QBCT].

129 Naama Rappoport et al., The Duffy antigen receptor for chemokines, ACKR1, - ‘Jeanne DARC’ of benign neutropenia, 184 British J. Haematology 497, 497 – 507 (2019).

130 See Macmillan, supra note 61.

131 Rukia S. Kibaya et al., References Ranges for the Clinical Laboratory Derived from a Rural Population in Kericho, Kenya, PLos ONE (2008).

132 Seung Ha Park et al., Biomarkers in HCV Infection, 70 Advances in Clinical Chemistry 131, 131 – 196 (2015).

133 For a robust discussion of the developing use of biomarkers in the drug safety context, see Steve Olson et al., Accelerating the Development of Biomarkers for Drug Safety (2009).

134 U.S. Food & Drug Admin., FDA Takes Important Steps to Increase Racial and Ethnic Diversity in Clinical Trials (2022).

135 Martha Hostetter & Sarah Klein, In Focus: Reducing Racial Disparities in Healthcare by Confronting Racism, The Commonwealth Fund (Sept. 22, 2018), https://www.commonwealthfund.org/publications/2018/sep/focus-reducing-racial-disparities-health-care-confronting-racism [https://perma.cc/985D-TXH5].

136 Off. of Mgmt. & Budget, Exec. Off. of the President, Standards for the Classifications of Federal Data on Race and Ethnicity (1995).

137 See Atallah-Yunes, supra note 53.

138 Todd Gersten, Low White Blood Cell Count, Medline Plus (April 28, 2021), https://medlineplus.gov/ency/patientinstructions/000675.htm [https://perma.cc/K7HG-KTHB].

139 Matthew M. Hsieh, et al, Neutrophil Count in African Americans: Lowering the Target Cutoff to Initiate or Resume Chemotherapy? 28 J. Clinical Oncology 1633, 1637 (April 1, 2010).

140 Valencia Higuera, What is a White Blood Cell Count?, Healthline (March 11, 2022), https://www.healthline.com/health/wbc-count [https://perma.cc/J7ZL-YRTP].