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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
Rights & Permissions [Opens in a new window]

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

Overview

In April 2022, the Food and Drug Administration (FDA) released a guidance document entitled “FDA takes Important Steps to Increase Diversity in Trials,” which was met with widespread support.Footnote 1 Public comments were received from more than sixty sources before the end of the comment period on June 12, 2022.Footnote 2 Based on the public response to the guidance, interest in increasing diversity in clinical trials appeared to be gaining national momentum. Expanding on previous industry guidance relating 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 health care experts across the nation.”Footnote 3

Given the unprecedented competing healthcare challenges on the 2022 midyear agenda,Footnote 4 such as reproductive health legislationFootnote 5 and the ongoing threats and complications of rapidly spreading communicable diseases,Footnote 6 exposure to public announcements on increasing diversity within clinical trials could have been easily overshadowed. However, the crux of this writing is to draw attention to the subject, largely because it impacts African Americans, a demographic in the United States that is disproportionately distressed with health care disparities.Footnote 7 Any glimpses of knowledge or medical discovery that could help to redress harm or reinforce a weakened familial-cultural infrastructure should be emphasized for sanative restoration of the impacted communities.

This Article focuses on the African American cohortFootnote 8 and its nexus to Benign Ethnic Neutropenia, or “BEN.” BEN is clinically identified as an absolute blood neutrophil count (ANC) of < 1.5 G/L.Footnote 9 More specifically, “BEN [is] defined as individuals of African ancestry with neutrophil counts <1500 cells/uL on at least two (2) laboratory tests, separated by at least 1 month, in the absence of infection (including negative testing for human immunodeficiency virus, hepatitis B or C, human T lymphotropic virus), nutritional deficiency, autoimmune disorders, or invasive cancer.”Footnote 10 BEN seems to be gaining traction in the genomic and hematologic research spheres. Efforts to mitigate healthcare disparities require well-planned clinical studies with various racial and ethnic populations, involving pathophysiology and treatment responses. Where differences are observed among population groups, clinical trials focused on these subpopulations are required.Footnote 11 In the author’s opinion, BEN is one such difference that necessitates specific clinical focus.

This Article endeavors to convey a harmonized approach to the examination of (1) the African American BEN cohort within the context of basic scientific understanding, (2) the interplay of applicable governing regulatory protections, and (3) increased clinical trial participation. The Article’s ultimate objective is to emphasize the need for increased diversity in clinical trials.Footnote 12

Introduction

Who is African American?

The U.S. census survey and other U.S.-based studies have established fine-scale, self-reported ethnicity distribution at the state and county level. The self-reported poll conducted by the U.S. Census Bureau’s most recent census accountings revealed that Black Americans comprise 13.4% of the overall U.S. population, contrasted with White/non-Hispanic individuals who account for sixty percent of the overall population.Footnote 13

Do these percentages reflect the actual racial and genetic composition of the U.S. population? The connection between actual genetic ancestry and self-reported region of ancestry can be tenuous.Footnote 14 Studies show that African Americans in the United States typically carry segments of DNA attributable to peoples of Europe, Africa, and the Americas, with variation in African and European admixture proportions across individuals and different groups across the country: according to a 23andMe survey, African Americans show average proportions of 73.2% African, twenty-four percent European, and 0.8% Native ancestry.Footnote 15 In this same survey, most individuals who had less than twenty-eight percent African ancestry identified as European American.Footnote 16 Further, in 2014, researchers examined another set of data on 145,000 DNA samples provided to the same 23andMe genetic testing company for ancestry analysis.Footnote 17 Findings revealed that at least six million Americans who called themselves “White” had at least one percent African ancestry. The majority of those with at least one percent African ancestry were found to be in southern states, with South Carolina and Louisiana being the predominant states.Footnote 18 Thus, an individual’s choice to self-identify as a “White” person does not necessarily negate the potential for them to be DNA-positive for BEN, because “mating between individuals with different continental origins, which we refer to here as ‘population admixture,’ results in individuals who carry DNA inherited from multiple populations.”Footnote 19

Additionally, human biologic variation is driven by genetic drift (random variation in allele frequency associated with ancestral lineages) and uncorrelated selection pressures.Footnote 20 This means that physical traits cannot be used to thoroughly delineate racial groups: traits such as skin color, tooth size, bone density, presence of hemoglobin S, and craniofacial measurements do not map to socially defined racial categories.Footnote 21 Our DNA is the true identifier of who we are biologically and scientifically; what we choose to call ourselves, or prefer to be called, within the confines of cultural humanity is a different narrative altogether. As long as racial classification data can be captured on query forms through self-declaration, the “race category [will simply be] a socially constructed grouping of humans based on shared physical or social qualities.”Footnote 22

Because this Article focuses partially on the racial identity of a “protected class” of individuals, which draws from categorical standards entitled Race and Ethnic Standards for Federal Statistics and Administrative Reporting formulated by the U.S. Office of Management and Budget (OMB) in 1977, inferences to race will stem from these currently established standard definitions.Footnote 23 OMB requires that race data be collected for a minimum of five groups: White, Black or African American, American Indian or Alaska Native, Asian, and Native Hawaiian or Other Pacific Islander.Footnote 24 From this perspective, racial identification is premised upon physical and social construct: these five categories leave little room for ambiguity, and require individuals to assign themselves to a discrete racial faction that may not reflect the realities of their ancestry or identity. OMB does, however, permit the Census Bureau to use a sixth category where respondents may report “Two or More Races,” which refers to “combinations of two or more of the following race categories: White, Black or African American, American Indian or Alaska Native, Asian, Native Hawaiian or Other Pacific Islander, or Some Other Race”.Footnote 25

Surely, the Census Bureau’s is not the most effective method for capturing race, which “has been a defining issue in American politics since before the country formally came into existence, a dividing line marked by generations of struggle and conflict.”Footnote 26 From the outset, these categories were never intended to reflect scientific aspects of race.Footnote 27 To this end, on June 15, 2022, Dr. Karen Orvis, Chief Statistician of the United States, made an announcement commencing a formal review to revise OMB’s Statistical Policy Directive No. 15 (Directive No. 15): Standards for Maintaining, Collecting, and Presenting Federal Data on Race and Ethnicity. Footnote 28 The revision is expected to be completed no later than Summer 2024.Footnote 29 In the interim, the customary government-based self-identification polls will likely continue to be used for federally funded clinical trials.

The question of how using these categories impacts those who are of African descent with a BEN diagnosis remains a focal point of the elusive discussion on increasing African American clinical study participation.Footnote 30 Following this Article’s exploration of the race-determination processes that are presently used in clinical trials is a brief review of the protections afforded to those of African descent prior to clinical trial participation. This review is followed by a discussion of legal protections available to research volunteers upon entering a federally funded clinical research study.

A Protected Class

“Protected classes” are a manifestation of how federal law conceptualizes protection against discrimination.Footnote 31 The term “protected class” refers to a group of people with shared characteristics (e.g., race, gender, age, disability, or sexual orientation) who enjoy special legal protections from laws, practices, and policies that aim to discriminate against them due to their shared characteristics. These groups are protected by both U.S. federal and state laws.Footnote 32

Race and color were the earliest protected classesFootnote 33 – in fact, they were the first protected classes officially recognized in the U.S‥Footnote 34 In 1866, President Andrew Johnson vetoed the Civil Rights Act, stating that “no such system as that contemplated by the details of this bill has ever before been proposed or adopted. They establish for the security of the ‘colored’ race safeguards which go indefinitely beyond any that the General Government has ever provided for the white race.”Footnote 35 A brash statement of this nature was apropos in the 1860s, as a post-Civil War nation grappled to embrace the ideologies of a recently ratified 13th Amendment to the U.S. Constitution, which freed a once enslaved population of people. Although freed under the letter of the law, the requisite legal protections needed to survive as “free” people were not yet in effect.

Fortunately, the 39th Congress voted to override Johnson’s veto, and the Civil Rights Act of 1866 went into effect. Congress believed the federal government had a duty to aid in shaping a new multiracial society in the postwar South.Footnote 36 The framers of the Civil Rights Act expressly intended to exercise plenary authority and to displace state law to the extent necessary to enforce the absolute rights of all Americans, not merely to provide equal rights under state law.Footnote 37 Key provisions conferred citizenship to all qualified individuals, precluding states from denying citizenship to those same individuals.Footnote 38 Because race determinants were solely based on physical characteristics, the authority of these laws impacted those who could be determined to be of the “colored” race.

The Civil Rights Act of 1866 was the first law to officially grant protective rights to those of African descent in the U.S. as a “race” of people. It was the first federal law to affirm all citizens are equally protected under the law.Footnote 39 The evolution of this initial enactment eventually led to the Civil Rights Act of 1964, which prohibited racial discrimination in places of employment, public facilities, transportation, etc.Footnote 40

Clinical trial study volunteers are afforded additional protections beyond those granted under the Civil Rights laws.Footnote 41 The Office of Human Research Protections (OHRP) is the primary source for protections that accompany participation in federally funded trials.Footnote 42 These protections are designed to identify and provide special regulatory support for “vulnerable” populations—children, pregnant women, trauma and abuse victims, incarcerated individuals, residents of mental facilities or those with a diminished capacity for assent, elderly individuals (greater than sixty-five years of age); economically disadvantaged individuals, and “subordinates of the researchers (students or employees).”Footnote 43 The OHRP has articulated the regulatory justification for protecting vulnerable populations as follows:

When some or all of the subjects, such as children, prisoners, pregnant women, handicapped, or mentally disabled persons, or economically or educationally disadvantaged persons, are likely to be vulnerable to coercion or undue influence, additional safeguards have been included in the study to protect the rights and welfare of these subjects.Footnote 44

Here, African Americans recruited to participate in clinical trials can be vulnerable to coercion based on age, may have a diminished capacity to consent, and may lack the requisite education to read and understand the informed consent form, among other considerations. Because numerous factors can influence the participation of any study candidate, including the African American cohort, it is crucial to give the utmost attention to protecting the legal rights of subjects in keeping with current regulations. Undiagnosed study candidates with BEN may or may not necessarily be considered “vulnerable.” Standardized pre-study criteria for African Americans, in general, would be a value-added best practices component for all federally funded clinical studies.

The FDA provides regulatory support for research participants through Title 21 of the Code of Federal Regulations.Footnote 45 Title 21 governs clinical trial execution through respective product release into mainstream commerce.Footnote 46 Study investigators and study teams must know when a subject has a special health condition, such as a low white cell count threshold, in order to position any study volunteer for optimum safety and protection throughout the duration of the study.Footnote 47

African genomes are humanity’s oldest and most diverse.Footnote 48 This diversity holds within it an almost unfathomable potential – from scientific breakthroughs to gene editing.Footnote 49 Studies of African genetic diversity have greatly informed our understanding of human origins and history, have identified genes under natural selection across evolutionary time, and hold great potential for elucidating the genetic bases of disease susceptibility and drug response among diverse human populations.Footnote 50 This fundamental knowledge has set the stage for the development of healthcare policies for working with healthcare disparities inherent to certain populations. All facilities in the United States that perform laboratory testing on human specimens for health assessment or the diagnosis, prevention, or treatment of disease are regulated under the Clinical Laboratory Improvement Amendments of 1988 (CLIA), which, among mandates, requires clinical laboratories to obtain certification from the Center for Medicare and Medicaid Services (CMS) before accepting and testing human samples.Footnote 51

Benign Ethnic Neutropenia (BEN)

BEN is an absolute blood neutrophil count (ANC) of < 1.5 G/L.Footnote 52 BEN is one of the most common causes of chronic neutropenia in individuals of African, Middle Eastern, and West Indian descent, but many physicians in the United States are not familiar with this benign condition.Footnote 53 These same populations can manifest chronic neutropenia without an increased risk of infection.Footnote 54 BEN needs to be differentiated from congenital neutropenia for this practice-altering reason and its presence should be tested for when individuals of certain ethnicities present with a persistent absolute neutrophil count below 1500μ/L in isolation, as well as in the absence of causes of secondary neutropenia, such that BEN is largely a diagnosis of exclusion.Footnote 55 It is important to note that this classification for BEN was developed largely in a Caucasian or White population: White individuals receiving chemotherapy and other immunosuppressive agents were the basis for the development of the parameters cited in the preceding definition.Footnote 56

The phenotype referenced as ANC has been the subject of research for more than eighty years.Footnote 57 For example, in 1941, Forbes et al. noted that neutrophil counts in healthy black sharecroppers in Mississippi were lower than those of white workers living under the same conditions.Footnote 58 And yet, standard laboratory values for white cell blood counts have remained unchanged in the United States.

Current literature reveals this condition to be the most common form of neutropenia in the world.Footnote 59 Adequate awareness of the condition by health care professionals should be compulsory to avoid both under- and over-evaluation.Footnote 60 In 2021, Macmillan et.al, revealed findings on gene variants linked to unnecessary bone marrow biopsies in African-Americans.Footnote 61 The results showed that several bone marrow biopsies that had been prescribed as a result of unknown etiologies for ANCs were unnecessary.Footnote 62 And the biopsies were normal for ninety-seven percent of patients with a certain neutrophil-lowering genotype:Footnote 63 Macmillan “essentially created this racial health disparity by not fully considering how genetic variation affects white blood cell levels … [their] study supports genotyping African Americans before performing a bone marrow biopsy for the indication of isolated low white blood cell counts.”Footnote 64

This strongly suggests a justification for increasing diversity in study participation concerning hematology reference ranges for varying ethnic populations.Footnote 65 About sixty-three percent of African Americans carry two copies of the gene variant that lowers neutrophil levels.Footnote 66 Adding to this complexity, the term “benign” as used in BEN is about the actual ANC status, which means that the individual assessed with BEN “is at a no greater risk of infection despite their neutropenia.”Footnote 67

Standardized methods for working with BEN where patients or trial volunteers present with serious co-morbidities are a work in progress. The recent enactment of the CHIPS and Science Act on August 9, 2022, promises to open up a plethora of options for training and educating minorities in scientific innovation.Footnote 68 The future of dealing with ANCs, real-time diagnostic implementations of discovery, and the establishment of best practices for addressing an ethnocentric health care need has just become brighter. Access to funding for the

… [p]rograms and grants to increase the transparency and accessibility of federal STEM education among Historically Black Colleges and Universities, Tribal Colleges and Universities, Hispanic-Serving Institutions, and other minority-serving institutions and to lower barriers to recruitment and advancement of women and minorities in STEM …

constitutes a significant step towards bringing greater clarity to medical conditions like BEN.Footnote 69 Moreover, the presence of BEN in children, younger adults, and older adults suggests a hereditary pattern for the condition.Footnote 70 More research is needed to fully comprehend this hereditary pattern.

While individuals confirmed to carry the gene variant are at no greater risk of infection than non-carriers, the potential “unknowns” are still in question, leaving much for researchers to explore concerning this diagnosis — especially in a pandemic context. To this end, this cohort can be considered “unprotected” as standardized methods for patient care management in health care crisis settings are lacking. Cohorts can be erroneously categorized and not allowed to participate in certain research studies due to their ANC: as recently demonstrated by Merz and colleagues, the number of neutrophils in individuals with BEN is adequate for the host defense, so it should be considered a normal variant and not a “condition” or “disease.”Footnote 71

Improved knowledge may help in optimizing therapeutic approaches due to the prevalence of BEN in those who willfully acknowledge African ancestry as well as those who do not. Thorough, thoughtfully crafted study protocols serving BEN cohorts are the pathways to the generalized knowledge needed to develop a standardized intervention for this subpopulation. This contention will be discussed again briefly in the “biomarkers” section.

Discussion

Human Research Protection

This Article challenges clinical trial stakeholders to become intentionally proactive without ethical compromise in recruiting African American study participants, and in this case, trial participants diagnosed with BEN or potential trial candidates of African descent without a known BEN diagnosis. Pairing cautious implementation of current human subject protections with scientifically sound biomarker testing is the formula for best practices when working with this cohort.

Congress’s first legislation to protect the rights and welfare of human subjects was the National Research Act, signed into law in 1974.Footnote 72 Contributing factors to the enactment of the National Research Act were rooted in the grossly unethical behaviors demonstrated in the Public Health Service Syphilis Study, including the Nuremberg Code, developed as an offshoot of the horrific experimentation perpetrated on Jews by Nazi scientists in 1945.Footnote 73 The National Commission for Protection of Human Subjects of Biomedical and Behavioral Research was created, which issued the Belmont Report, best known for emphasizing the principles of respect for persons, beneficence, and justice in the domain of human research:

  • • Respect for Persons – subjects should be provided an informed consent containing all the information a reasonable person would need to decide to participate;

  • • Beneficence – risks, and benefits of research are disclosed to prospective subjects as part of the consent process; and

  • • Justice – selection process should be equitable and all the risks and benefits should be made known—and included in the informed consent.Footnote 74

The advent of the Federal Policy for the Protection of Human Subjects, better known as the “Common Rule,” has become the foundation for the ethical treatment of research subjects in federally funded trials. Administered under the Office of Human Research Protections (OHRP), these governing rules were adopted in 1991 by fifteen federal departments and agencies, including, subsequently, the Social Security Administration by statute and the Central Intelligence Agency by executive order.Footnote 75

Individuals diagnosed with BEN wishing to participate in clinical trials should look to the Common Rule for the regulations in effect regarding their safety and legal rights as research participants. All rights of a research subject should be explicitly memorialized in the research site’s informed consent form that correlates with the matching Institutional Review Board-approved study protocol. Further, all documents and succeeding document versions outlining participant study responsibilities should be approved by the Institutional Review of the Board of Record before being provided to the subject.Footnote 76 Indeed, regulations governing federally funded trials mandate that the informed consent form be publicly posted.Footnote 77 In other words, research study content accessibility and transparency are required by law.

The FDA has the potential to further these important objectives. The FDA became, in effect, a law enforcement organization after Congress passed the Food and Drugs Act in 1906.Footnote 78 After that, legislation progressively demanded greater accountability for marketing food and drugs and the need for testing drugs in clinical trials increased.Footnote 79 Today, the FDA regulates clinical investigations of products such as drugs, biological products, and medical devices. The FDA is not considered a Common Rule agency because its regulations differ from the Common Rule. Still, the FDA is required to harmonize with the Common Rule whenever permitted by law as noted in the 21st Century Cures Act.Footnote 80

Study Enrollment Qualifiers

Methods for patient solicitation generally include the evaluation of specific qualifying identifiers in the form of eligibility criteria, more frequently referenced as “inclusion” and “exclusion” study criteria.Footnote 81 Occasionally, promises of monetary or other compensation are utilized to enhance participation. Rarely do advertisements for study enrollment lead with statements that define the purpose of the research from a regulatory point of view.

Federal regulations define research as “a systematic investigation, including research development, testing, and evaluation, designed to develop or contribute to generalizable knowledge.”Footnote 82 Expanding the information base of a hypothesis, a scientific inquiry, or a medical condition should be the ultimate objective of clinical research. This Article argues for prescription of a regulation-based formula for attaining generalizable knowledge through increased enrollment of BEN participants in the clinical trial domain.

To solicit study participation, intentional language should be used to attract potential participants: the importance of artistry and animated delivery of the typical clinical study appeal repeats itself time and time again. Regardless, even the slightest indicators of study advertisements must be approved by the jurisdictional Institutional Review Board;Footnote 83 strict adherence to OHRP guidelines must be employed when soliciting study volunteers. This author suggests that enrollment processes for those with BEN should be carefully crafted in advance of study starts, and recommends that the race self-identification process begin immediately after execution of the IRB-approved informed consent form. Knowledge gained from this initial process could give substantial direction toward the ongoing direction of the overall trial.

Consistent with OMB Policy Directive 15, and as discussed above, the categories of racial classification are social-political constructs and should not be interpreted as scientific or anthropological. The standards have been developed to provide a common framework for uniformity and consistency in the collection and use of data on race and ethnicity by Federal agencies.Footnote 84 Because of this, additional information beyond OMB race classification data points may prove useful when stratifying for BEN study volunteers.

Inclusion criteria function to specify the characteristics for study entry, such as stage of disease or specific pathophysiological characteristics.Footnote 85 As such, the qualifying criteria below may provide a recommended starting place when attempting to differentiate between BEN and non-BEN study volunteers:Footnote 86

  1. 1. The participant self-identifies as African American or of African Descent;

  2. 2. WBC Laboratory values are deemed abnormal (if revealed as a result of a protocol inclusion or exclusion requisite)Footnote 87; or

  3. 3. There is a documented history of an abnormal neutrophil count absent cause or with cause.Footnote 88

Positive confirmation of two out of three of these criteria could potentially support baseline measures for capturing preliminary data in the identification of BEN participants irrespective of the type of trial being conducted or the subject’s ethnicity.Footnote 89 It is the author’s opinion that without this suggested method for capturing potential BEN candidates, their prospective contribution as BEN volunteers could be overlooked. This method of tiered screening is a more all-inclusive approach, without regard for the race categorization currently used with federal OMB standards.Footnote 90 The benefits of this approach are two-fold:

  1. 1. If using self-identification race polls based on the current US Census model, it may be resourceful to utilize a type of scaffolding algorithm to document race and ethnicity categories with more accuracy. Otherwise, individuals who qualify as White as supported by the U.S. census “White” grouping category, could subsequently contribute towards inherently biased outcomes data.Footnote 91

  2. 2. Studies pursuing BEN-related research-based data will benefit from a comparable carefully crafted algorithm as noted in bullet one. Capturing the definition that best suits the study volunteer further contributes to the scientific validity of the dataset and could accurately enhance the ethnicity profile of the research study overall. Genotyping subjects for rs2814778-CC as a part of the inclusion criteria adds the requisite authenticity for valid race-based scientific analyses. Harmonization between census-driven racial categorizations and genotypes is a promise of standardized technological advancement for the clinical trial industry not yet materialized—but highly possible.

Since the inception of the census in 1790, the race categories utilized have been geared towards the White race as a reflection of the times (“Free White Males over 16, Free White Males under 16, Females, all other Free People, and Slaves”); initially, Native Americans did not have their own category.Footnote 92 Inclusivity characterizations were an outgrowth of the dominant political power. Merging census classifications with adequately defined culturally sensitive population descriptors, as opposed to the current heavily influenced political biases, proffers the study volunteer a show of respect and justice when considering trial participation—and justice, as the Belmont Report articulates, is of crucial import in the clinical study context.Footnote 93 In keeping with bottom-line census thinking where Middle Eastern and other populations are concerned, a possible algorithm for the identification of BEN candidates could include a scaffolding approach with the self-identification process:

  1. 1. According to the US Census, do you self-identify as White?

    ‘If yes, please move to question 3:

  2. 2. According to the US Census, do you self-identify as Two or More Races’?

    ‘If yes, please move to question 4:

  3. 3. If you self-identify as White does your ancestry include origins in (please check all that apply):

    • • North Africa ___

    • • Middle East ___

  4. 4. If you self-identify as Two or More Races does your ancestry include origins in (please check all that apply):

    • • Africa ___

    • • Black Ethiopian Jews ___

    • • Middle East ___

    • • West Indian ___

    • • Yemenite Jews ___

Utilizing an approach like this one would serve as a safety net for potential BEN clients whose patient histories reveal white cell counts below normal ranges. If the aim is to increase a specific diversified enrollment type, removing known contributors to hidden barriers is essential. With more than sixty-three percent of African Americans carrying two copies of the gene variant, more than half of the African American population has a nexus to this condition.Footnote 94 Increased enrollment thus expands stratification opportunities for greater discovery and understanding of BEN and its impact on co-morbidities or ancillary health care conditions.

Research studies conducted by the U.S. military could potentially provide some useful data regarding BEN, if the studies were carefully constructed to the needs of BEN subpopulations. The federal government has jurisdiction over the military, making the application of the referenced regulations pertaining to human subject protection in clinical research accessible and pronounced, including collection of data on race and ethnicity.Footnote 95 Investigators in the military are required to follow federal regulations pertaining to military-based study volunteers. African Americans have a significant presence in the military. When examining a sample of U.S. military veterans in 2020, Black soldiers comprised approximately twenty-one percent of the active-duty Army, fifteen percent of the Army National Guard, and twenty-one percent of the Army Reserve. Black Americans have served in the Army at a rate that is higher than their representation in the U.S. population.Footnote 96 In 2019, the total number of Black or African American veterans in the U.S. was around 2.15 million, representing around twelve percent of the total veteran population.Footnote 97

From 2019 to 2045, the racial and ethnic composition of veterans will change.Footnote 98 Population research projects that the proportion of veterans who are Non-Hispanic White will decrease from seventy-four percent to sixty-one percent.Footnote 99 For Black veterans, the statistics of participation will increase from twelve percent to fifteen percent.Footnote 100 This provides the military an opportunity to take the lead on the much-needed research surrounding this condition. To further support the rationale behind these trials being conducted in government-based settings, or public-private health care settings for added transparency of supporting trial sources, a two-decade analysis of 20,000 U.S.-based trials registered with ClinicalTrials.gov found that fewer than forty-four percent of the trials reported any race or ethnicity data.Footnote 101 Other findings show that industry-funded trials reported less ethnicity data when compared to U.S. government-funded studies.Footnote 102

However, there is at least one significant regulatory downside to military personnel participating in clinical studies with genomic components:

The Genetic Information Nondiscrimination Act (GINA) of 2008 protects Americans from discrimination based upon their genetic information in both health insurance (Title 1) and employment (Title ll). The health insurance protections of GINA extend to private health insurers, Medicare, Medicaid, Federal Employees Health Benefits, and the Veterans Health Administration. For the U.S. Military’s TRICARE insurance program, GINA offers more limited protection. TRICARE may not use genetic information for coverage, underwriting, or premium-setting, but eligibility for TRICARE insurance is contingent upon employment by the U.S. Military, and GINA’s employment protections do not apply to the U.S. Military. The US Military is permitted to use genomic and medical information to make employment decisions.Footnote 103

Regardless of military affiliation, though, securing reliable data on individuals with BEN is crucial to the mitigation of health care disparities. Due to its prevalence in certain ethnicities, BEN should be deemed an important investigative research platform for health care institutions across the United States until adequate clinical and regulatory standardizations have been scientifically developed and appropriately implemented. Clinically based standardizations of this caliber are the types of clear manifestations of the measurable gains to be had with streamlined outgrowths of generalizable knowledge.

To enhance equity for those who may be financially challenged and who do not have military coverage, newly enacted laws such as H.R.913, entitled the Clinical Treatment Act, promotes access to life-saving therapies for Medicaid enrollees by ensuring coverage of routine patient costs for items and services furnished in connection with participation in qualifying clinical trials.Footnote 104 This pivotal move by Congress, which went into effect on January 1, 2022, expands the reach of social justice for over 41.6 million Medicaid beneficiaries to now participate in certain clinical trials while having study-related costs covered.Footnote 105

Lastly, the National Cancer Institute (NCI) of the National Institute of Health (NIH) has published standard definitions for adverse events (AEs), which is the system used to gauge the severity of toxicities for subjects participating in oncology studies or any other federally funded trials involving hematology and oncology.Footnote 106 These criteria are used for the management of chemotherapy administration and dosing, and in clinical trials to provide standardization and consistency in the definition of treatment-related toxicity.Footnote 107 AE reporting is mandatory in clinical research to ensure patient safety and to understand the toxicity profiles of treatments.Footnote 108 Therefore, methods for collecting this information must be accurate and scientifically reliable.Footnote 109 The end goal is to increase clinical trial participation for African Americans with standards that support safety as well as greater survival rates.

In September of 2019, Atallah-Yunes et al. pointed to a distinct difference in breast cancer survival rate detection between African Americans and Whites, stating that “[a]side from health care discrepancies and socioeconomic factors, the difference has also been theorized to be related to the lower baseline ANC in African Americans that lead to more frequent dose reductions and discontinuations in chemotherapy treatments, and, therefore, lower survival rates.”Footnote 110 The thinking here is that there is a good chance that survival rates for African Americans could potentially be indirectly related to a discontinuity in treatment. Additionally, lower ANCs could be equally challenging for this same population as a result of an initial lowered threshold baseline, even without the impact of chemotherapy-involved disease states.

As study candidates pursue the possibility of enrollment with unconfirmed BEN statuses, they may or may not be entered into a trial based on their standing neutrophil count as interpreted by varying knowledge bases and opinions of study investigators. For example, when using the NCI toxicity scale, an ANC of less than 1.5 × 109 cells/L defines the upper limit of grade two toxicity and has become the minimum threshold at which to begin therapy in many clinical trials.Footnote 111 This upper limit of grade two toxicity is historically based on the risk of inducing a prolonged state of neutropenia after administering myelosuppressive cytotoxic chemotherapy.Footnote 112 If a potential subject presents with this grade of toxicity prior to enrollment, there is a good chance the individual may not be enrolled in the respective study. On the contrary, if a potential volunteer is a confirmed BEN candidate, uninformed study staff may still have conflicting views on how best to work with the study candidate - if at all. The grade two toxicity scale, as defined, does not account for neutrophil biology and may not be relevant to BEN.Footnote 113

It is the author’s opinion that this current system could present threshold complexities for a subject attempting to enter a study with a confirmed status of BEN, if indeed they are granted acceptance at all. For example, in January 2017, researchers gathered data on 401 interventional prostate cancer clinical trials. Findings revealed 47.9% (192) required participants to have an ANC of 1.5 × 109 cells/L or higher which resulted in 41.4% of prostate cancer clinical trials excluding black male patients with BEN.Footnote 114 Herein lies the need for increased knowledge with respect to standardized race-based clinical laboratory determinants.

This includes future studies to determine whether special neutrophil count thresholds are [also] necessary to avoid unnecessary dose reductions and discontinuation of medications with cancer trials.Footnote 115 Tools, such as biomarkers, may help to streamline the discovery process.

Biomarkers

Biomarkers are characteristics of the body that can be measured, such as a gene, protein, or other substance found in blood, bodily fluids, or cells.Footnote 116 The FDA-NIH Biomarker Joint Leadership Council developed a Working Group in 2015 that defined a biomarker as

[a] defining characteristic that is measured as an indicator of normal biological processes, pathogenic processes, or biological responses to an exposure or intervention, including therapeutic interventions. Biomarkers may include molecular, histologic, radiographic, or physiologic characteristics.Footnote 117

The Working Group’s definition notes specifically that biomarkers are not “measure of how an individual feels, functions, or survives.”Footnote 118 The Working Group also denotes and defines specific categories of biomarkers in its definition: susceptibility/risk biomarkers,Footnote 119 diagnostic biomarkers,Footnote 120 monitoring biomarkers,Footnote 121 prognostic biomarkers,Footnote 122 predictive biomarkers,Footnote 123 response biomarkers,Footnote 124 and safety biomarkers.Footnote 125 The NCI provides a considerably simpler definition, defining a biomarker (also “called [a] molecular marker and signature molecule” Footnote 126) “[a] biological molecule found in blood, other body fluids, or tissues that is a sign of a normal or abnormal process, or of a condition or disease.” The NCI elaborates that “a biomarker may be used to see how well the body responds to a treatment for a disease or condition.”Footnote 127

The white cell blood count (WBC), or the neutrophil count, is an example of a biomarker, one that is frequently used in determining a research volunteer’s BEN status. Biomarking testing for BEN exceeds the scope of the WBC when genotyping. Rules for governing human subject protection in genomic clinical trials are located on the National Human Genome Research Institute website.Footnote 128 Confirmatory genotyping for rs2814778 (again, also referred to as “ACKR1”) could serve as a fundamental basis for identifying and isolating subjects with distinct hematologic laboratory values.

Targeting those with the rs2814778-cc genotype gives assurance of locating subjects who are at no greater risk of infection than any other cohort, essentially declaring that BEN is benign. An important caveat to these findings exists, however: Rappaport et al. state that there have been reports of neutropenic individuals without the typical ACKR1 SNP, indicating that some familial neutropenia might be due to other mutations that cause low ANC—in addition to the possibility of other ANC influences from other genetic traits.Footnote 129 The benefits of genotyping thus afford researchers the ability to develop studies with the propensity to hone in on health care disparities with keener precision. In this vein, MacMillan emphasizes a noteworthy quote from Vanderbilt researcher Mosely: “Genetic variation has a large impact on the levels of biomarkers like white blood cell counts, but reference ranges are defined based on population averages without taking genotypes into account.”Footnote 130

Current approved laboratory values utilized in the United States have been grossly impacted by those of European ancestry, and the majority of immuno-hematological and clinical chemistry reference ranges are based on North American or European data.Footnote 131 A dedicated investment of resources, time, and effort is required for laboratory values to be adjusted across the Americas. As research technology advances, laboratory ranges based on genotypes will be more exacting and much for definitive for the global health care network.

Moreover, the improper use or interpretation of biomarkers can be detrimental in both clinical and research settings by misdirecting therapy or research activities. Biomarkers can be critical guides for treatment regimens and can be predictors of treatment responses as in the case when a genotype becomes the defining marker.Footnote 132 If biomarkers are to be used properly, there needs to be an understanding of their sensitivity and specificity, how and in what contexts to use them, how to interpret them in those various contexts, and how to properly validate them.Footnote 133

Conclusion

Making progress in increased trial participation utilizing targeted laboratory tests that are inclusive of specialized genomic biomarkers will require more than scientific procedures developed to identify a precise condition. It also involves the recognition and respect of a people who, by law, are a protected class of individuals marked by a historical pattern of egregious acts of abuse and discrimination in the United States. Protected yet unprotected is a reality for many who call themselves African American and who currently reside in the United States; encouraging individuals of African descent to consider trial participation entails helping them to understand how best to navigate through the health care system, which has not always had their best interest at heart. As such, respecting the race/nationality of each study volunteer is important. Using data collection forms that are culturally competent while scientifically sound encourages confidence in participation. Helping to educate respective study volunteers regarding the scientific movement that’s happening concerning their ANC status shows dedication and commitment. Enlarging the importance of their participation without coercion demonstrates leadership - with a willingness to inform. BEN research study participants are the true change agents for future learnings here. As willing subjects, they are the catalyst needed to (1) update and redefine misguided laboratory values, and (2) hone in on the untapped role that more knowledge of BEN may play in race-driven survival rates.

A commitment of all stakeholders to become adequately informed of the inherent condition manifested by this cohort of individuals is crucial for public and private health care partnerships that continue to express an interest in promulgating needed next-generation laws and policies to be effectively enacted. According to FDA Commissioner Robert M. Califf, “The U.S. population has become increasingly diverse, and ensuring meaningful representation of racial and ethnic minorities in clinical trials for regulated medical products is fundamental to public health … [g]oing forward, achieving greater diversity will be a key focus throughout the FDA. ”Footnote 134 Greater diversity should yield increased enrollment of underrepresented populations, such as those impacted by BEN. Increased enrollment should in turn lead to generalizable knowledge that boomerangs back into the community of those vested in its very existence and future. Increased enrollment will ultimately open the doors for increased diversity in research team players, administrators, and sponsors.

Increased diversity enrollment will not come without a price. Trials involving biomarkers, such as what is needed for scientific validation of BEN subjects and other special ethnic populations with medical nuances, carry an added burden of sensitivity. Learning to properly navigate through the human subject protection process using unconventional pathways is crucial when working with vulnerable or underrepresented populations as experienced with BEN volunteers. A willingness to explore these possibilities lessens the imputation of misconduct, such as subtle or openly displayed racially charged discriminatory practices laced with clear acts of deception, by those being entrusted to study intrinsic medical anomalies.

For health care workers, scientists, educators, and purveyors of the law, these concerns cannot be glossed over or mitigated. There is a long history in medicine of using healthy White men as the standard for “normal,” ascribing anything different as abnormal, other, or requiring adjustments. A healthy respect for how best to lift and protect African Americans as well as other ethnic populations is essential to visualizing a diverse increase in clinical trial participation. It is incumbent upon professionals working in the various domains of health care and health law to partner together and become adequately informed relative to the populations they serve. One of the first obstacles encountered will be that most organizations do not have a shared definition of racism, making racism difficult to even discuss: if one person thinks that racism is merely people saying mean things to each other while another person sees it as a system of advantage based on race, it will be impossible to co-design any solutions together.Footnote 135 Footnote Ultimately, however, clinical trial sponsors and supporting administrative and investigative team members should not shy away from surmounting these and other obstacles in order to thoroughly examine trial attributes for diversity inclusion in advance of study execution.

Table 1. (OMB - Race)Footnote 136

Table 2. Salient Features of BENFootnote 137
Table 3.

In general, an adult who has fewer than 1,000 neutrophils in a microliter of blood have neutropenia. Fewer than 500 neutrophils in a microliter of blood, is called severe neutropenia. With this, even the bacteria normally living in a person’s mouth, skin, and gut can cause serious infections.Footnote Footnote 138

However, from the standpoint of science, specifically neutrophil physiology, the absolute number of circulating neutrophils as measured in routine blood tests reflects a small number of the available pool of biologically active cells. Approximately half of the biologic pool of neutrophils outside the marrow are circulating; the other half marginate to vascular endothelium. Because of this, minor reductions in the neutrophil count should be of no clinical significance or cause for infection. Footnote 139

For the most part, normal ranges can vary by laboratory. The laboratory performing the test may include a reference range listed on the patient report. Footnote 140

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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.

4 Stacey Hughes, Industry Voices Facing Unprecedented Challenges, America’s Hospitals, and Health Systems Need Help Now, Fierce Health Care (Aug. 26, 2022), https://www.fiercehealthcare.com/hospitals/industry-voices-facing-unprecedented-challenges-americas-hospitals-and-health-systems [https://perma.cc/YN76-45VP].

5 2022 Midyear Report—Gaining Ground: Proactive Legislation in the States, Nat’l Institute for Reproductive Health (July 18, 2022), https://nirhealth.org/resources/2022-midyear-report-gaining-ground-proactive-legislation-in-the-states/ [https://perma.cc/F4B7-MS9Y].

6 See Hughes, supra note 4.

7 See Christian E. Weller & Lily Roberts, Eliminating the Black White Wealth Gap is a Generational Challenge, CAP (Mar. 19, 2021), https://www.americanprogress.org/article/eliminating-black-white-wealth-gap-generational-challenge/ [https://perma.cc/FPN2-UG6T].

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).

10 Rahul Lakhotia et al‥ Natural history of benign ethnic neutropenia in individuals of African ancestry, 77 Blood Cells, Molecules, & Diseases 12, 12 (2019).

11 Anne L. Taylor & Jackson T. Wright, Importance of Race/Ethnicity in Clinical Trials: Lessons From the African-American Heart Failure Trial (A-HeFT), the African-American Study of Kidney Disease and Hypertension (AASK), and the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), 112 Circulation 3654, 3654 – 3666 (2005).

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].

13 ‘Quick Facts, U.S. Census Bureau (July 1, 2022), https://www.census.gov/quickfacts/fact/table/US/PST045221 [https://perma.cc/A8C2-QH9F].

14 Katarzyna Bryc et al., The genetic ancestry of African Americans, Latinos, and European Americans across the United States, 96 Am. J. Hum. Genet. 37 – 53 (2015).

15 Id. at 42.

16 Id. at 44.

17 Blue Telusma, Study Proves Southern White People Have More Black DNA Than Those in the Rest of the U.S., The Grio (Dec. 22, 2014), https://thegrio.com/2014/12/22/study-southern-white-people-more-black-dna/ [https://perma.cc/KN6L-V622].

18 Id.

19 Id.

20 Andrea Deyrup & Joseph L. Graves, Racial Biology and Medical Misconceptions, 386 New England J. of Med. 501, 501-03 (2022).

21 Id.

22 Lauren E. Merz & Maureen Achebe, When Non-Whiteness Becomes a Condition, 137 J. of Blood 13-15 (2021).

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

24 Explanation of Data Standards for Race, Ethnicity, Sex, Primary Language, and Disability, U.S. Dep’t of Health & Hum. Servs, Off. of Minority Health (May 18, 2021), https://minorityhealth.hhs.gov/omh/browse.aspx?lvl=3&lvlid=54#:~:text=The%20OMB%20minimum%20categories%20for,Other%20Pacific%20Islander%2C%20and%20White [https://perma.cc/22YQ-4R3Q].

25 U.S. Census Bureau, Race (2022), https://www.census.gov/quickfacts/fact/note/US/RHI325221 [https://perma.cc/V3R3-GC27].

26 Dan Balz, The Politics of Race are Shifting, and the Politicians are Struggling to Keep Pace, Wash. Post (July 5, 2020), https://www.washingtonpost.com/graphics/2020/politics/race-reckoning/ [https://perma.cc/2QAB-MKDT].

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

28 Karin Orvis, Reviewing and Revising Standards for Maintaining, Collecting, and Presenting Federal Data on Race and Ethnicity, The White House (June 15, 2022), https://www.whitehouse.gov/omb/briefing-room/2022/06/15/reviewing-and-revising-standards-for-maintaining-collecting-and-presenting-federal-data-on-race-and-ethnicity/ [https://perma.cc/6J7E-RDAM].

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].

32 Robert Longley, What is a Protected Class? Thought Co. (June 11, 2022), https://www.thoughtco.com/what-is-protected-class-4583111 [ https://perma.cc/HZ9J-6MGM].

33 Akhil Reed Amar & John C. Harrison, The Privileges or Immunities Clause, Interactive Const. (2022), https://constitutioncenter.org/interactive-constitution/interpretation/amendment-xiv/clauses/704 [https://perma.cc/SRP2-6YED].

34 Longley, supra note 32.

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

36 Civil Rights Act of 1866, Ballotpedia (last visited Apr. 4, 2023), https://ballotpedia.org/Civil_Rights_Act_of_1866#Later_developments [https://perma.cc/4N3M-FKPE].

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].

Figure 0

Table 1. (OMB - Race)136

Figure 1

Table 2. Salient Features of BEN137

Figure 2

Table 3.