Diversity in clinical trials still lags
In addition to age, sex, diet, underlying disease, and the concomitant use of other medications, race and genetic factors may play pivotal parts in the variability of subjects' responses to a medication. Regrettably, minority groups are underrepresented in most clinical trials. Often, there are insufficient data to assess the effectiveness or safety of new drugs in members of minority groups, especially Blacks. Concern about this issue led the National Institutes of Health and the Food and Drug Administration to establish guidelines encouraging the inclusion of more women and minority groups in clinical trials. However, it is uncertain whether these guidelines are being implemented and whether the participation of minority groups in clinical trials has increased (King, 2002).
This opening paragraph from a 2002 editorial in the New England Journal of Medicine raised the alarms over the lack of sexual, gender, and racial diversity in clinical trials and the lagging effort being put into correcting the issue over two decades ago. Regrettably, women and minority groups are still vastly underrepresented in most clinical trials in 2023—a scourge that plagues clinical testing and trials across virtually every segment of the medical industry.
A prime example of this lack of diversity exists in the world of HIV prevention:
In 2019, Gilead Sciences announced that they had received approval from the U.S. Food and Drug Administration (FDA) to prescribe Descovy (emtricitabine/tenofovir alafenamide, FTC/TAF) for use as part of a Pre-Exposure Prophylaxis (PrEP) regimen to prevent the transmission of HIV…except for use in people assigned female at birth (Gilead Sciences, 2019).
The primary advantages of using TAF in a PrEP regimen over the previously approved Truvada (tenofovir disoproxil fumarate, TDF) are that TAF is simply a better, safer drug. TAF is absorbed more quickly than TDF and produces higher levels of the active drug in cells, meaning it can be given in smaller doses, leading to lower levels of exposure to the kidneys and less bone density loss—some of the biggest concerns related to the use of TDF as PrEP which led to higher rates of drug discontinuation (Hill, et al., 2018).
And yet, despite the fact that roughly 19% of new HIV diagnoses occurred in women in 2019 (Centers for Disease Control and Prevention, 2022), Gilead Sciences fundamentally failed to successfully include women in their clinical trials to ensure that the drug was effective in “…individuals at risk from receptive vaginal sex” (Gilead Sciences). This resulted in Descovy receiving a black box warning—the strictest labeling requirement that the FDA can mandate for prescription drugs that highlights serious and sometimes life-threatening adverse drug reactions—which essentially precluded over half of the U.S. population from being prescribed the drug.
This lack of diversity isn’t unique to the field of HIV; it extends to every aspect of the medical field, from vaccines to therapeutic drugs to medical devices. This lack of inclusion of essentially anyone other than young and middle-aged men of European descent in testing and trials has created a landscape where commonly used and relied upon vaccines, therapies, and medical devices are administered to patients without any real knowledge of whether or not they are as effective—or even effectively at all—across patient demographic populations.
Another example resides in a widely accepted piece of standard medical equipment: the pulse oximeter. This easy-to-use device measures the saturation of oxygen in the blood by using a cold light source that shines a light through the fingertip, analyzes the light from the light source that passes through the finger, and determines the percentage of oxygen in the red blood cell. Unfortunately, it works poorly on people with non-white skin:
A retrospective cohort study released in the Journal of the American Medical Association Internal Medicine found that compared to white patients, “…Asian, Black, and Hispanic patients had a higher adjusted time-weighted average pulse oximetry reading and were administered significantly less supplemental oxygen for a given hemoglobin oxygen saturation compared with white patients” (Gottlieb, et al., 2022).
To put that in lay terms, non-white patients had higher readings from pulse oximeter devices than white patients because of the way that light penetrates skin tissue, and as a result, received less supplemental oxygen than white patients.
This disparity was particularly important to consider during the height of the Coronavirus 2019 (COVID-19) global pandemic when Black, Hispanic, and American Indian patients were much more likely to contract, experience worse symptoms of, be hospitalized for, and die from COVID than White patients (Tai, et al., 2022). As a respiratory disease, COVID-19 required patients to be placed on respirators in an effort to sustain and save lives, and there were (and still are) serious concerns that relying upon pulse oximetry readings resulted in minority patients receiving inadequate levels of supplement oxygen compared to white patients.
Continuing on the topic of COVID-19, minority patients were overwhelmingly underrepresented in both the Pfizer BioNTech and Moderna mRNA vaccine studies:
Across the three Pfizer trials, over 80% of participants across every age group (12-15 years, 16-25 years, and 18+ years) were white, while Black patients represented only 3-9% of participants, Asians 1-8%, American Indians/Alaska Natives (AI/AN) 0-6%, and Hispanics 3-20%.
Across the four Moderna trials, over 79% of participants across every age group were white, while Black patients represented 0-10%, Asians 1-5%, AI/AN 0-2%, and Hispanics 0-18% (Khalil, et al., 2022).
Khalil, et al., found that this lack of diversity essentially mirrors similar vaccine trials during the development of the H1N1 vaccine in 2009. After the H1N1 pandemic, much handwringing occurred across the U.S. medical establishment over the low uptake of vaccination among minority populations, particularly Black and Hispanic people. Little attention was paid at the time, though, to the vast disparity in H1N1 vaccine trials, in which 91% of participants were white (Khalil, et al.). The majority of studies published about this lack of diversity were not published until 2021 and 2022…in the wake of the COVID-19 vaccine trials.
So, how do we fix what is clearly a broken system? The answers seem simple:
As referenced in the opening paragraph of this piece, federal guidance has been in place since the 1990s “encouraging” increased recruiting of diverse patient populations, and those guidelines have been updated since that time.
Minority Health and Health Disparities Strategic Plan 2021–2025 (National Institutes of Health, 2021).
But time is money in the pharmaceutical and medical device industries, and most companies are simply either unwilling to invest the time, effort, and resources to recruit significantly diverse patient populations when it’s far more profitable and expedient to work with an easily accessible and willing white population that is perceived to be more compliant with the requirements of trials (and this, also, is a biased belief).
The truth is that many companies too often fall back on the beliefs that there are too many cultural barriers to overcome in order to recruit Black, Hispanic, and AI/AN patients for clinical and device trials, that it’s too costly to actively try to overcome those barriers, and that the patients are “difficult to deal with” during the process. These biases persist despite many of the scientists, themselves, involved in these trials being from racially and ethnically diverse backgrounds. Why invest these resources when you can bring a vaccine, drug, or device to market with FDA approval much faster by using the “reliable” population?
The reason they must invest is that the consequences of their failure to diversify result in the loss of human lives. When these companies fail to live up to their duty to fully test their products, minority populations pay the price. If they are not going to willingly do so, then the FDA needs to step in and institute minimum participation requirements in order to receive approval, even if that means the upheaval of existing “norms” around the approvals process.