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)

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.

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. ¹ Public comments were received from more than sixty sources before the end of the comment period on June 12, 2022. 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.” ³

Given the unprecedented competing healthcare challenges on the 2022 midyear agenda, ⁴ such as reproductive health legislation ⁵ and the ongoing threats and complications of rapidly spreading communicable diseases, 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. 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 cohort 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. 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.” 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. 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. 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. 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. 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. ¹⁵ In this same survey, most individuals who had less than twenty-eight percent African ancestry identified as European American. 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. 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. 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.” ¹⁹

Additionally, human biologic variation is driven by genetic drift (random variation in allele frequency associated with ancestral lineages) and uncorrelated selection pressures. 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. 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.” 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. 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. 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”. 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.” ²⁶ From the outset, these categories were never intended to reflect scientific aspects of race. 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. ²⁸ The revision is expected to be completed no later than Summer 2024. 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. 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. 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. ³²

Race and color were the earliest protected classes ³³ – in fact, they were the first protected classes officially recognized in the U.S‥ 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.” 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 13^th 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 39^th 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. 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. ³⁷ Key provisions conferred citizenship to all qualified individuals, precluding states from denying citizenship to those same individuals. 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. 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. ⁴⁰

Clinical trial study volunteers are afforded additional protections beyond those granted under the Civil Rights laws. ⁴¹ The Office of Human Research Protections (OHRP) is the primary source for protections that accompany participation in federally funded trials. 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).” 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. 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. ⁴⁵ Title 21 governs clinical trial execution through respective product release into mainstream commerce. 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. ⁴⁷

African genomes are humanity’s oldest and most diverse. ⁴⁸ This diversity holds within it an almost unfathomable potential – from scientific breakthroughs to gene editing. 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. 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. ⁵¹

Benign Ethnic Neutropenia (BEN)

BEN is an absolute blood neutrophil count (ANC) of < 1.5 G/L. 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. ⁵³ These same populations can manifest chronic neutropenia without an increased risk of infection. 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. 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. ⁵⁶

The phenotype referenced as ANC has been the subject of research for more than eighty years. 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. 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. ⁵⁹ Adequate awareness of the condition by health care professionals should be compulsory to avoid both under- and over-evaluation. ⁶⁰ In 2021, Macmillan et.al, revealed findings on gene variants linked to unnecessary bone marrow biopsies in African-Americans. ⁶¹ The results showed that several bone marrow biopsies that had been prescribed as a result of unknown etiologies for ANCs were unnecessary. ⁶² And the biopsies were normal for ninety-seven percent of patients with a certain neutrophil-lowering genotype: 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.” ⁶⁴

This strongly suggests a justification for increasing diversity in study participation concerning hematology reference ranges for varying ethnic populations. ⁶⁵ About sixty-three percent of African Americans carry two copies of the gene variant that lowers neutrophil levels. 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.” 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. 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. ⁶⁹ Moreover, the presence of BEN in children, younger adults, and older adults suggests a hereditary pattern for the condition. 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.” 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. 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. 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. 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. 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. ⁷⁶ Indeed, regulations governing federally funded trials mandate that the informed consent form be publicly posted. 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. ⁷⁸ After that, legislation progressively demanded greater accountability for marketing food and drugs and the need for testing drugs in clinical trials increased. 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 21^st Century Cures Act. 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. 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.” 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; 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. 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. ⁸⁵ As such, the qualifying criteria below may provide a recommended starting place when attempting to differentiate between BEN and non-BEN study volunteers: 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) ⁸⁷; or

3. 3. There is a documented history of an abnormal neutrophil count absent cause or with cause. 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. 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. 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. 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. 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. 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. 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. 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. 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. ⁹⁷

From 2019 to 2045, the racial and ethnic composition of veterans will change. ⁹⁸ Population research projects that the proportion of veterans who are Non-Hispanic White will decrease from seventy-four percent to sixty-one percent. ⁹⁹ For Black veterans, the statistics of participation will increase from twelve percent to fifteen percent. 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. ¹⁰¹ Other findings show that industry-funded trials reported less ethnicity data when compared to U.S. government-funded studies. 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. 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. 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. 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. 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. ¹⁰⁷ AE reporting is mandatory in clinical research to ensure patient safety and to understand the toxicity profiles of treatments. ¹⁰⁸ Therefore, methods for collecting this information must be accurate and scientifically reliable. 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.” 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. 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. 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. 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. 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. 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. 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. ¹¹⁷

The Working Group’s definition notes specifically that biomarkers are not “measure of how an individual feels, functions, or survives.” ¹¹⁸ The Working Group also denotes and defines specific categories of biomarkers in its definition: susceptibility/risk biomarkers, ¹¹⁹ diagnostic biomarkers, ¹²⁰ monitoring biomarkers, ¹²¹ prognostic biomarkers, ¹²² predictive biomarkers, ¹²³ response biomarkers, ¹²⁴ and safety biomarkers. ¹²⁵ The NCI provides a considerably simpler definition, defining a biomarker (also “called [a] molecular marker and signature molecule” 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.” 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. 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. 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.” 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. 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. 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. 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. ” 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. ¹³⁵ 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) ¹³⁶

Table 2. Salient Features of BEN 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. 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. 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. ¹⁴⁰