What color is your clinical trial? - (5/1/2021)

By Dr. Ron Gasbarro

Do Black people metabolize drugs the same way White people do? Does it matter if you come from Europe or Asia? Are there medications that some humans can tolerate while others should not be prescribed because of genetic differences?

If you believe that all men – and all women – were created equally, then welcome to the topsy-turvy world of drug metabolism. When a drug enters your body, it goes to work, alleviating your headache, treating your cancer, or stopping your infection. What happens after it does its job? It wants to get the hell out of Dodge. It wants to leave your body, whether it is through your urine or your feces. Most drugs pass through the liver, which is the primary organ for drug metabolism. Once in the liver, enzymes convert active drugs to inactive forms. The liver's primary mechanism for metabolizing drugs is via a specific group of cytochrome P-450 enzymes.

Not everyone's P-450s work that same way
Human cytochrome P-450 (CYP) 3A4 is the most abundant hepatic and intestinal phase I enzyme that metabolizes approximately 50% to 75% marketed drugs [Zhou, 2008; Bumpus, 2021]. These enzymes work by slapping a positive atom, radical, or electron on the drug molecule or kicking off a negative one., thereby giving the drug a ticket to ride out of your body. 

However, depending on one's ethnicity, these enzymes can work extremely fast or amazingly slow when they metabolize various drugs. And it is harder to identify these people. For example, White just does not mean white. White means British, Turkish, Swiss, German, and so on. Hence, Brits, Swiss, and Poles are poor metabolizers, while Turks and Spaniards are ultra-rapid metabolizers of certain drugs [Bernard, 2006]. The same goes for Black people, whereby Ethiopians are ultra-rapid metabolizers, and South Africans and Ghanaians are poor metabolizers. Poor metabolizers can experience a greater potential for drug-drug interactions and side effects. Ultra-rapid metabolizers have higher rates of drug elimination and, thus, a potentially lower drug efficacy. 

The drugs involved run the gamut from antidepressants, and analgesics, to chemotherapeutic agents and antiarrhythmics. Such varying metabolic activity can have clinical importance as more drugs are added to a patient's regimen and the consequent risk of drug interactions increase.  

Health disparities have been long recognized
In the United States, health disparities are well documented in minority populations such as Black Americans, Native Americans, Asian Americans, and Latinos [Health Ohio, 2004]. There are many causes for the existence of health disparities—from physiological to socioeconomic. These disparities result in an inequity of favorable clinical outcomes. Example: European Americans die more often from cardiovascular disease and cancer than Native Americans, Asian Americans, or Hispanics [Hummer, 2004]. Black Americans are 2 to 4 times more likely to develop clinical Alzheimer's disease than Caucasians [Ighodaro,2017]. Asian Americans are at higher risk for hepatitis B, liver cancer, and tuberculosis [Chen, 1995]. Black Americans have higher mortality rates than any other racial or ethnic group for 8 of the top 10 causes of death [Hummer, 2004]. Reasons for these imbalances range from genetic to environmental to having access to healthcare. 

The design of clinical drug trials has been a problem 
According to John Lechleiter, former Chairman, President, and Chief Executive Officer of Eli Lilly and Company, the ethnic diversity gap is woefully dismal when analyzing clinical trials aimed at diseases disproportionately impacting minority populations. He notes that Black American men are twice as prone to succumb to prostate cancer as White Americans [Mahal, 2018]. Yet, they represent a mere 4% of prostate cancer clinical trial subjects [Shenoy, 2016]. Suicide is one of the top three causes of death among Asian American women under 45 years of age; this group represents only 1% of trials for potential major depressive disorder therapies. Also notable, while diabetes prevalence among Mexican Americans and Puerto Ricans is more than twice that of Caucasians, those cohorts combined represent barely 4% of diabetes trial patients [Heron, 2011; Xu, 2010].

Injustice in clinical trials – The "Black and White" dilemma
Disparities in health among Black and White Americans have existed for hundreds of years [Clayton, 2001]. Black Americans and other minorities experienced maltreatment, neglect, and denial of healthcare compared to the white population. Example: The Spanish influenza pandemic of 1918. An estimated 500 million people, or one-third of the world population, became infected with this virus. The number of deaths was estimated to be at least 50 million worldwide, with about 675,000 fatalities occurring in the United States. Black communities were either denied care or received inadequate attention [CDC, 2018]. Even in the modern era, although no longer legally enforced, cultural segregation is still one of the primary causes of racial disparities in health because it dictates socioeconomic status by controlling access to training and employment opportunities [Williams, 2001]. Even though Black American health status and outcome are gradually advancing, Black health has generally stagnated or deteriorated compared to whites since 1980 [Clayton, 2001]. 

The Tuskegee experiment
The Tuskegee study was another leading illustration of health disparity among Black Americans [Olansky, 1954]. In 1932, the Public Health Service, working with the Tuskegee Institute in Alabama, began a study to document the natural history of syphilis in hopes of justifying treatment programs for Blacks [Corbie-Smith, 1999]. It was called the "Tuskegee Study of Untreated Syphilis in the Negro Male." 

The Tuskegee study involved 600 Black men, 399 with syphilis and 201 with no disease [Corbie-Smith, 1999]. Researchers explained to the men they were being treated for "bad blood," a term used in the study to describe several ailments, including syphilis, anemia, and fatigue. Researchers and health professionals told the men that they would be pivotal in a study to treat their current conditions. Health workers monitored the subjects who were only given placebos such as aspirin and mineral supplements, even though penicillin became the recommended treatment for syphilis in 1947, some 15 years into the study. The study subjects later discovered they were lied to by the researchers. This study resulted in a class-action lawsuit citing lack of consent, deceptive information, and medical neglect. By July 1972, when the study ended, over 100 participants had died, 40 spouses were diagnosed with syphilis, which was passed to 19 children at birth. The study revealed a lack of medical treatment and discrimination among Black people [Olansky, 1954]. Even in the 21st century, Black Americans are disinclined to participate in clinical trials [Friemuth, 2001].

The study became the longest nontherapeutic experiment on humans in medical history [Corbie-Smith, 1999]. This abomination has come to represent the mistreatment of Blacks and the potential for abuse of any population that may be susceptible because of race, ethnicity, gender, disability, age, or social class. Healthcare professionals who will be caring for an increasingly diverse America must understand the lasting implications of this study for their patients. 

Tuskegee results in COVID-19 vaccine distrust
Memories of the Tuskegee experiment still haunt the Black American population. Recent data show that although Black Americans comprise 13% of the US population, they encounter 21% of deaths from COVID-19 but only 3% of enrollees in vaccine trials [Warren, 2020]. This inequity threatens both the strength and the generalizability of the trial results. It is also of particular concern in vaccine trials, in which differences in environmental exposures can result in differences in immunologic responses that could affect both safety and efficacy. 

What are the barriers to greater participation of Black people in COVID-19 trials? Although multifactorial, a key factor is the profound and warranted lack of trust that many Black Americans have for the general health care system and, notably, clinical research [Warren, 2019]. This suspicion is often traced to the legacy of the infamous Tuskegee experiment. However, the distrust is far more deeply rooted, in centuries of well-documented examples of racist exploitation by American physicians and researchers [Warren, 2020]. With the FDA approval of COVID-19 vaccines, their success in Black and other populations will be based on whether members of these communities trust that they are safe and effective and believe that the organizations offering them are honorable. 

Identifying the right drug for the right race
The use of race may become a valuable means of identifying therapeutic populations. By using race as an alternative for genetic variation in targeting patient populations, pharmaceutical companies may bypass the need for pricey pharmacogenomic testing. BiDil (hydralazine hydrochloride and isosorbide dinitrate) is an antihypertensive combination approved in 2005 by the US Food and Drug Administration (FDA) for use by self-identified Black Americans. The formulation is a prime example of ethnic-based pharmacology. In explaining the drug's effectiveness among Black Americans, Nitromed Inc. (Lexington, MA), the original manufacturer of BiDil, cites platelet nitric oxide (NO) insufficiency, a "distinctive pathophysiology found primarily in African American patients."  The lack of NO promotes vasoconstriction instead of vasodilation, increasing the risk of stroke and other cardiovascular events. BiDil is said to improve survival, prolong the time to hospitalization for heart failure, and improve patient-reported functional status [BiDil PI, 2019; Lee,2005].  Arbor Pharmaceuticals, LLC, Atlanta, GA now owns this product.

Happy "trials" to you
Unfortunately, minority groups are underrepresented in most clinical trials [Bumpus, 2021]. Often, insufficient data exist to assess the efficacy and safety of new drugs among members of minority groups [King, 2000]. Concern about this issue led the NIH and FDA to establish guidelines encouraging more minority participants in clinical trials. 

In addition, new techniques are being devised to augment minority enrollment in clinical trials. Intervention mapping (IM) is a system designed to modify the behaviors of recruitment coordinators and specialist investigators to increase diversity in trials [Amorrortu, 2018]. Using IM, recruitment interventions that focus on building relationships with minority-serving physicians will hopefully encourage minority patient referrals. 

For better pharmaceuticals, diversify clinical trials.
Subtle genetic variables can alter P450 enzymes in people with some gene variants more dominant in specific ethnic groups. The altered enzyme could affect how drugs are processed and used by the body so that what works for one person could be inadequate or toxic for another [Bumpus, 2021]. Because most clinical drug trials include people of European descent and fewer people of African, Asian, or Latin descent, disparities in drug effectiveness are often not uncovered until the drug has been out in the open market for a while. 

These findings may force drug manufacturers to move toward a tomorrow where "treatments are most likely to work for all people" and "existing health disparities are not further exacerbated" [Bumpus, 2021].

Ron Gasbarro, PharmD, is a recovering pharmacist and writer-in-residence at Rx-Press.

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