Disparities in clinical trial enrollment persist, fortified by the foundation and historical ideologies undergirding clinical cancer research. The scientific community has an ethical responsibility to seize the current moment to deconstruct and reconstruct these paradigms for more equitable research.
A recent editorial (1) observed that leading up to the National Cancer Act of 1971, advisers from the National Panel of Consultants on the Conquest of Cancer issued a “remarkably prescient” statement about the trajectory of cancer research speculating, “the long-term future may belong to the immunologist and the geneticist…” (2). We have seen this prediction come to fruition as scientific discovery and technological innovations merge. Advancements in multiomics tools, technologies, and approaches (e.g., genomic, transcriptomic, metabolomic, proteomic, and epigenetic) are driving molecularly focused research, seeing cancer as a genomic disease with unique signatures and potential pathways to target. The field has moved beyond tumor cells, refocusing on the tumor microenvironment via stromal and immune cells, increasing knowledge of cell-to-cell interactions that catalyze and proliferate cancers. Bioinformatics and big data advance our abilities to analyze more complex clinical and molecular data that spark new strategies to turn immune cells into a line of defense attacking cancer cells, among other breakthroughs (3). Bolstered by the Precision Medicine Initiative and the 21st Century Cures Act President Barack Obama established, these new paradigms have led to precision medicine and immunotherapy rapidly becoming bedrocks of clinical research, continuously informing discoveries, predictive and prognostic models, and trial designs that help reconceptualize tumorigenesis and progression, therapeutic resistance, and drug development.
In that same April 1970 congressional report, Texas Senator Ralph W. Yarborough invokes another equally prescient proclamation: Cancer cuts across all levels and segments of our population. It deals out death and suffering regardless of wealth, color, or creed, and to find its ultimate solution will require a concerted effort of all those who have been affected by it or who might be in the future. That means every one of us (2).
This demonstrates a pervasive, persistent problem in cancer research. The committee does not recognize disparities resulting from compounding systemic social issues that have tangible, yet different impacts on specific populations, exacerbating cancer burdens and hindering survival. However, embedded in their long-term vision for a better future for cancer research lies the pressing need for a more equitable approach wherein scientists and physicians collaboratively engage communities in, across, and beyond disciplines, institutions, and even social systems as research partners, including everyone who is or will be affected by the disease.
Today, most clinical cancer researchers and providers understand cancer disparities as a real problem—even while debating the root causes—but even now progress can wane when it comes to moving beyond discussions of disparities to actions that generate and implement more inclusive frameworks for health equity. Disparities are part and parcel of foundational structures that have unintended or intended consequences, benefiting some at the expense of others. A hard reality is that we have to break the cycle of saying we need change but upholding the structures and ideologies that perpetuate disparities because “it's too hard” to deconstruct and reconstruct how, why, and for whom we conduct research.
CALLS TO ACTION TOO OFTEN DEFERRED
Understanding social and environmental determinants including race, gender, occupation, socioeconomic status, education, and geography as drivers of social injustice is not new. History has stalwart fighters who have addressed biases, racism, and oppression that permeate medical science and health care. For over a century, numerous African-American leaders, activists, physicians, scientists, and philosophers emphatically solicited calls to action to address disparities. In 1906, W.E.B. Du Bois argued that sickness and mortality rates among Black populations are “an indication of social and economic position…largely matters of condition and not due to racial traits and tendencies…” (4). In 1915, Booker T. Washington initiated the Negro Health Improvement Week public health campaign to address disparities in health care literacy, which he saw as integral for fostering health, economic success, and social mobility (5). In 1924, physician Algernon Jackson argued that investment in individual health presents a “virgin field for the righteous immortalization of some good, unbiased American to establish a foundation for the study and improvement of health, social and economic conditions among Negroes” (6). At the March 1966 Convention of the Medical Committee for Human Rights, Martin Luther King Jr (as cited in Dittmer, 2009) pronounced that “of all the forms of inequality, injustice in health care is the most shocking and inhumane” (7). These only scratch the surface of challenging racist social and scientific paradigms.
Moving forward, many academics, physicians, legislators, community organizers, institutions, consortia, and other stakeholders across research, industry, nonprofit, government, and other sectors echo these sentiments. Adamantly, they declare that changes in public policy, community engagement, and the philosophies undergirding why we seek cancer cures can chip away at some of the documented disparities in clinical research, albeit slower than we may like.
We know how to do this and have had the tools for a long time. Sustaining the commitment to do it is the hardest part. Standing at the crossroads of a new era of precision medicine and immunotherapy, we can shape what the next 50 years can look like by being more deliberate and equitable in how we bring cures into our communities.
RESTRUCTURING THE SCIENCE BY SITUATING THE SELF
Better science stems from challenging what we know (or think we know) about clinical cancer research and care and the paradigms upon which it is built. This means integrating the interactions between systemic structures and social determinants into clinical research, seeing them as key drivers for social and environmental justice and filling the cracks in our scientific foundations with lived experience.
Wittingly or unwittingly, we bring our lived experiences to bear in how we conduct clinical research. Good science does not mean divorcing experience from research. Rather, merging diverse experience with methodologic frameworks strengthens clinical research. As a Black man, for instance, lived experience reminds me that the immunotherapy discoveries I make will not affect the community in which I was born and raised, and if they do, the field will have moved on to the next cutting-edge terrain that will bypass my community or come far later than it should. Integrating that knowledge into my scientific approach is how I understand what “discovery” and “better outcomes” really mean and how to achieve them.
Merging the personal and political with the scientific method (mistakenly assumed to be objective) situates the self within research to see inquiries and approaches more reflexively and transparently. This constant recontextualization and reconstitution is lived experience for marginalized groups whose voices need to be heard and elevated to address clinical research disparities, especially when it comes to trial enrollment or lack thereof. Only then can the field account for the complex variables operating unequally in scientific practice.
But this does not apply to only minorities, women, individuals in lower socioeconomic brackets, and other population subgroups left out or exploited by science. Historically, clinical research has been driven by and in service to white men. This dominant group must accept and state openly that they have been afforded privilege by systems of power and inequality, explicitly recognizing their privilege as just that, not as natural, neutral, or a norm to which others are compared. This is not an accusation; it is a fact and an ethical obligation. The entire cancer research community must embrace these complex experiences, whether benefiting from advantages or circumscribed by oppression, as informing the very ground upon which we scientifically stand. Then, we can address the disparities that hinder scientific progress to redefine what equitable science really is and ensure discoveries for all, not the few. We see this divide very clearly in clinical trial enrollment, and addressing this is paramount to advance cancer discovery and equity.
ENROLLMENT MATTERS
Clinical trials are the most powerful mechanisms to drive discoveries and reduce cancer burden. Trial participation offers patients more advanced treatment options with meticulous protocols that they would not have access to otherwise. Clinical trials are essential for developing new drugs and novel therapeutics and testing safety and efficacy, providing an evidence-based rationale for FDA approval. Precision medicine and immunotherapy trial designs generate data that inform the development of predictive and prognostic models that can be integrated into personalized treatment regimens (8). Most importantly, as standard practice, clinical trial results are widely generalized and applied to patients.
However, research examining clinical trial representation shows that enrollment does not represent the diversity of the U.S. population. Racial and ethnic minorities, patients from lower socioeconomic status, those in rural areas, and other subgroups make up a far smaller portion of trial participants despite bearing disproportionate cancer incidence and mortality (9). The 2020 AACR Cancer Disparities Progress Report showed that the U.S. population is rapidly changing, becoming more diverse, as is the population of patients with cancer, but enrollment in clinical trials is not keeping pace (10–13). Studies have outlined disparities in pancreatic cancers and other cancer types, including breast, colorectal, lung, and prostate cancers, as well as common cancer trials and surgical oncology trials (14). Most of these studies are comprised largely of white patients, so they have disproportionate benefits, providing cutting-edge care to that population but not so much underrepresented minorities.
Many factors contribute to these gaps. Pragmatically, we need data. We cannot understand why certain groups are hit harder without data representing them and being able to make sense of it, thus empowering underserved patients and improving health care delivery. We know that underrepresented groups suffer more issues with access to trials based on limited financial resources, lack of insurance, and geography. Put simply, many patients cannot afford treatment; taking time off from work and expensive, frequent travel for treatment is untenable (15). The bench-to-bedside model does not work if we cannot get patients to the bedside or bring the bedside to their neighborhoods. Additionally, some studies show lack of awareness can hinder participation among these groups (16); however, other research indicates racial and ethnic minority patients often demonstrate willingness to participate in trials, so this problem could be overemphasized (17). Language and cultural barriers impede trial participation. Another crucial barrier is a deep, persistent mistrust stemming from historic racism and exploitation of minorities in medicine that prevents minorities from buying into clinical trials. Longstanding data bias compounded by providers’ perception of underrepresented populations’ reluctance can lessen provider tendencies to offer trials as a treatment option. Disparities in health care education and health literacy further complicate participation (16). These varied social determinants present complex, overlapping barriers that must be better understood to fill marked gaps in trial enrollment.
All this matters for patients’ lives and for the impact clinical research has as a whole. When we conduct trials that have disproportionate benefits while “othering” underrepresented populations, we exacerbate disparities and treat our patients unequally and unethically. Biased trial data lead to FDA approval based on generalizations that may harm patients because the studies do not adequately address safety and efficacy for these groups. Medical treatments confined to ivory towers cannot work, and addressing this mistrust is an uphill battle in communities of color. We know clinical trials save lives, but with the current predominant structures in which we generate science, we can only save the lives of some. Instead of enacting the Hippocratic oath, clinical trialists and providers can actually do harm by not increasing trial enrollment among these populations (16).
BEYOND TICKING A BOX
Fostering diversity in clinical research means more than ticking a box to meet a benchmark. It means a foundational shift that seems overwhelmingly daunting or aspirational. But we do not have to build anew; pragmatically we can leverage existing infrastructures. For instance, new NCI Cancer Center Support Grant guidelines require rigorous community outreach and engagement and a new “diversity, equity, and inclusion” component. This presents opportunities not only to speak about these concepts as pillars of academic cancer research excellence but also to operationalize them. For example, like most cancer centers, Virginia Commonwealth University Massey Cancer Center works with the state Department of Health, informing Community Needs Health Assessments and cancer control. Recently, though, we reached out to individual Health District Directors in our large 66-locality catchment area and found that they are often left out of conversations despite being the public health representatives who understand their communities best. Let's face it—we cannot be everywhere. We must engage others to help. These new partnerships with district directors are helping us better cover our catchment, broaden access to research and treatment for the underserved, and fill key data deserts and blind spots. In turn, this informs how we train the next generation of cancer physicians and scientists to enhance data aggregation and dissemination in our communities. Through these collaborations, we are developing more nuanced data capture that drives richer conversations about community need, garnering more usable, useful data for intervention, not just postmortem analyses. As an academic cancer center, it is incumbent upon us to do this work if we are to move beyond existing research models and extend outside the walls of academia to develop real research partnerships.
LEVERAGING MOMENTUM
Absolutely, we should capitalize on landmark advances in cancer research, but we have a unique opportunity to leverage our current moment. COVID-19 illuminated disparities we see in clinical research, as Black, Hispanic, and low socioeconomic status populations suffered more burden. The global pandemic reinforced that trust matters, and we still have a lot of work to build the science of trustworthiness.
But it also showed us how change can happen (18). Industry, academia, and policy makers moved past barriers that often limit collaboration to deliver rapid screening and prevention. Providers and researchers were forced to think on our feet and develop creative ways to address disparities like access. All this maps onto clinical research structures, paradigms, and practices so that we do not leave certain people behind.
The scientific community must embrace the changing tide arising from collectively bearing witness to George Floyd being murdered…for nearly 9 minutes at the hands of those who vowed to protect and serve, as well as continued, violent oppression of people of color that proliferates our screens. We cannot be complacent and go back to the familiar scientific status quo that limits the impact of discoveries and, ultimately, regresses clinical research.
We must generate paradigm shifts more often. For instance, I am working to disrupt the dominant focus on DNA with ZNA, drilling down to the zip code level to garner deeper knowledge about drivers of disparities in cancer burden and clinical trial participation. Shifting the focus from genetics and biology demonstrates how social and environmental determinants also situate patients and their cancers.
Collectively, the research community must act, to rebuild scientific infrastructures and practices that reflect our lived realities. Basic, clinical, translational, and population sciences have to work hand-in-hand. Moreover, we must commit to restructuring the values undergirding what we do and why we do it. Without this commitment, cancer research will continue to circumscribe discovery, serving only those who can afford innovation. Heathy equity must be our foundation, not isolated to a specialized field. This will provide the vital opportunity to grow and galvanize a community of stakeholders that move from the bench-to-bedside model to one working beside one another. Perhaps then we can rise to the challenge to build a scientific community that includes, as Yarborough and others espouse, “every one of us” (2).
Authors’ Disclosures
No disclosures were reported.
