Equity in Clinical Research: From Trials to Treatment

J Clin Pathways. 2022;8(4):16-21. doi:10.25270/jcp.2022.5.2

Health inequities among specific population subgroups have long been identified as a major deficiency of the US health care system. In principle, there is a societal consensus that everyone should have a fair and just opportunity to achieve healthy outcomes. However, there is no consensus on how to achieve this, stemming in part from the reality that the effort requires the coordi­nated actions of multisector institutions. These institutions each play different roles in—not only the provision of health care—but the development and distribution of novel and more effective treatments. Additionally, institutional incentives and priorities for promoting health equity may differ and at times misalign.

During the past several years, health equity has been of heightened focus for health care delivery systems and those who deliver care to diverse populations. But it has also become a priority for research funding organizations, including public and private agencies and foundations. In addition, many pharmaceutical and medical device companies have made commitments to address health inequities as they exist in the realm of clinical trials. To achieve equity in clinical research, we must implement mechanisms to broaden access to trials, employ differential methods to increase engagement among people from underrepresented groups, develop metrics and standards to facilitate equitable inclusion and transparency, and implement policies aimed at increasing access to novel and effective treatments after they are brought to market. We discuss some of the obstacles, solutions, and implications for widespread efforts to improve health equity throughout the clinical research cycle.

Introduction

Clinical trials, often sponsored by industry, are designed to test the efficacy or effectiveness of novel drugs and devices. They can be a beacon of hope for many families struggling with terminal illness, chronic conditions and medical maladies that greatly affect their course of life, impede their daily activities and reduce quality of life. A large body of evidence has shown that many debilitating and severe clinical conditions, including sickle cell anemia, asthma, type 2 diabetes mellitus, obesity, sexually transmitted diseases, infant mortality, tuberculosis, and COVID-19, are more prevalent in groups that have been minoritized and marginalized.^1-6 Patients in these subgroups bear a disproportionate burden of disease and would arguably stand to benefit the most from medical treatment breakthroughs and innovation achieved through clinical trials research compared with groups that are less affected or at lower risk. Yet historically, minority populations have been underrepresented in clinical trials.^4,7-9 

Ensuring equitable access to, participation in, and benefit from clinical trials is important for several reasons. First, par­ticipation can provide frequent follow up, better disease management¹⁰, unique and exclusive access to novel therapies, and, for some patients, a chance at survival. Indeed, there is evidence to suggest that people who take part in clinical trials have better health outcomes.^11,12 Second, for pivotal trials, it is vital that participants represent the population that is affected by the disease because the treatments in these studies can potentially lead to far-reaching changes to the treatment landscape. Third, trials are a venue for the collection of data that can further our understanding of the disease biology—the more di­verse the population, the more we are able to learn. Fourth, if the trial sample is diverse, it will help to sustain the generalizability of the findings to the population as a whole. Fifth, conducting a study in an ethnically diverse cohort provides opportunities to undertake subgroup analyses to determine if ethnic origin is associated with variation in the effectiveness of the intervention. 

In 2010, the US Food and Drug Administration (FDA) established the Office of Minority Health and Health Equity (OMHHE) with a mission to promote and protect the health of diverse populations through research and communication of science that addresses health disparities.¹³ Recently, the OMHHE launched an initiative^14,15 to enhance equity in clinical trials by identifying barriers to clinical trial enrollment for underrepresented populations (including, but not limited to, ethnicity, race, age, disability and geography); improving data collection and data quality for underrepresented populations in clinical trials; employing innovative strategies, trainings, education, and communication methods to increase clinical trial enrollment for underrepresented populations; and increasing training for diverse clinical trial investigators and other researchers. Despite this excellent progress, we recognize that much work is needed to realize these goals. In this article, we outline some of the obstacles and potential solutions.

Given the importance of achieving equity in clinical trials, there is an urgent need for researchers, industry, patient advocates, clinicians, and health systems to work together in partnership toward this end. This need resonates across these stakeholder groups and has the support of Pharmaceutical Research and Manufacturers of America (PhRMA), a group that has made a commitment to work toward “clinical trials infrastructure that addresses health disparities and closes the gap in clinical trial diversity to better reflect the intended treatment population.”¹⁶ In November 2020, PhRMA member companies launched the first-ever industry-wide principles on clinical trial diversity.¹⁷ In the quest for equity in clinical research, we must consider the entire process of drug and device development and testing and, more importantly, the process of dissemination after treatments are found to be effective. To do this, we must commit to developing mechanisms to increase access to trials, improve methods of engagement for underrepresented groups, create metrics intended to promote equitable inclusion, and, finally, implement policies to increase access to novel, effective therapies after they are approved and brought to market. 

Mechanisms to Increase Access to Trials

Although most serious medical conditions are treated in community settings, most clinical trial participation happens in academic research institutions (hospitals) or well-resourced, sometimes private, hospital settings¹⁸, which are frequently out of reach for those who are most vulnerable or most affected by the conditions they seek to improve. As early as the 1960s, this phenomenon was described by White and colleagues in their seminal “Ecology of Medical Care” paper. In this work, the authors presented a framework for the organization of health care demonstrating that less than 1% of at-risk populations are referred to academic medical centers.^19,20 The existing barriers and disparities in access to health care—stemming from social determinants of health and structural societal factors, that differentially impact people from groups that have been minoritized—often prevent those same individuals from participating in clinical research trials. While some programs focus on providing support for those who are socioeconomically disadvantaged, these programs may involve relocation and disruption to family life that can be a deterrent to participation due to lack of childcare, economic pressures or other social factors that make it challenging to participate (eg, National Institutes of Health Clinical Center, MD Anderson Cancer Center, St. Jude)^21-23 Although it is a place to start we cannot simply create ways for disadvantaged individuals to participate in trials on our terms. Instead, we must meet people where they are, and to do that we must understand where they are. 

Recently, industry-based drug and device companies have supported the need to increase socioeconomic diversity and representation in clinical trial participation. However, good intentions alone will not accomplish this. Rather, we need to build targeted mechanisms for increasing access in communities with the highest need and the greatest barriers. For these reasons, we must include members of the community in discussions about the design of the trial.

In the past 10 years, there have been many successful examples of community input into the design of clinical trials, but it has been most often in behavioral trials.^24-27 It is time to incorporate the lessons learned from these types of trials and apply them to drug and device trials. In a recent example, Day, et. al. used crowdsourcing to obtain community input for the design of a human immunodeficiency virus (HIV) phase 1 trial to examine the safety and effectiveness of combining a dose of an HIV antibody (VRC07–523LS) with vorinostat, a drug used to reactivate latent virus in HIV-infected individuals.²⁷ The authors found that the crowdsourcing method was helpful on several fronts. First, it provided an opportunity to introduce the trial to the community from which recruitment would be conducted. Second, it allowed the research team to incorporate community wants and needs into the design, including the informed consent and protocol processes. This also allowed the integration of culturally appropriate practices and the application of health literacy principles into the development of all patient-facing materials. Third, it helped to promote engagement and ownership of the research. Finally, the feedback was useful for designing future HIV trials.²⁷

Methods to Increase Engagement in Trials 

Even with equitable access among a diverse pool of potential participants, recruiting some subgroups into research studies remains a challenge and often results in lower representation among people from groups that have historically been minoritized and socioeconomically disadvantaged. In addition to historic mistrust of the health care system among some racial/ethnic groups, there exists a well-founded mistrust of health sciences research. The sensitivity around research conduct and participation among people from underrepresented populations stems from prior misdeeds dating back to the birth of the nation²⁸, including more recent examples as the well-known Tuskegee Syphilis trials^29-34, and the creation of the popular HeLa cell line, taken without permission from the cancer cells of Henrietta Lacks in the 1950’s.³⁵ Additionally, non-Eurocentric cultural perspectives, economic and geographic barriers can serve as deterrents to engagement and extended participation.

There is growing recognition of the need for support and intentional action to increase engagement among diverse groups. Key elements to overcoming these barriers include transparency and investment in relationship building, as well as community-engaged approaches accompanied by a conscious and intentional effort to meet prospective patients where they are and where they live. It takes an investment in community outreach, communication campaigns, formative work with the community members, and cultivation of community partnerships to build trust and overcome obstacles to participation. 

In 2021, Congress passed the Henrietta Lacks Enhancing Cancer Research Act of 2019, which among other things, directed the Government Accountability Office to “complete a study reviewing how federal agencies address barriers to participation in federally-funded cancer clinical trials by individuals from underrepresented populations and provide recommendations for addressing such barriers.” ^36,37 Also in 2021, PhRMA and the Deloitte Center for Health Solutions (CHS) issued a report, “Enhancing Clinical Trial Diversity: Stakeholder Perspectives on Advancing Research Through Representative Clinical Trials,“ outlining five critical strategies for enhancing diversity in clinical trials during the research and development of new medicines (Figure 1).¹⁷Creating a network of clinical trial sites in underserved communities could be accomplished by the collaboration of trialists across institutions for studies in many therapeutic areas. Such networks could potentially be called upon for assistance with enrollment in new trials, and over time, assuming trust is further established, the network could grow to facilitate diverse participation in multiple therapeutic areas. The development of a diverse pool of investigators and staff requires support and funding to ensure that students from groups that have been historically minoritized and socioeconomically disadvantaged are given an equitable chance to succeed in the educational programs that provide the appropriate training. The last three tasks concern community outreach and nurturing and sustaining the relationships that are essential to creating a lasting, trusting relationship between scientists and the communities they serve.

Achieving these goals will require partnership—including collaborations with the FDA, which has control over the regulations for diversity in clinical trials. Regulations set by government agencies may pose a challenge as they are at times not aligned with resource and time-intensive methods required to recruit members of society who are potentially less accessible. The FDA released draft recommendations to increase clinical trial diversity.³⁸ The draft guidance includes a proposal for broadening the racial and ethnic recruitment pools for clinical research, and offers an opportunity for feedback from the community.  “The Plan,” as it is named in the proposal, is flexible in that it allows for an assessment of the landscape of the disorder in terms of potential differential safety or effectiveness by race and ethnicity.  This is a great first step toward the goal of equitable clinical trials as it includes the recognition that there are other underrepresented populations defined by other demographic characteristics.

Metrics to Ensure Equitable Inclusion and Transparency

It is not possible to achieve equity in clinical trials without a means to measure progress. We must develop new metrics or adapt existing ones to help establish recruitment goals, monitor progress, and ultimately advise us when we have reached equity in representation within our trials. The metric(s) must be designed to determine that we have enough representation for a given patient population to account for the disproportionate burden of the condition for a given trial. While we may have equality of recruitment in mind, in which we would outreach to equal proportions of each racial/ethnic subgroup, it may be necessary to adjust these goals such that we oversample certain subgroups and deploy resources disproportionately to ensure adequate representation in our final trial sample.³⁹ In fact, it may be warranted to recruit proportionate to the longer-term outcomes of the disease or disorder—such as rates of mortality—that often are disproportionately higher for minority subgroups. In this situation, there might be a larger proportion of a subgroup than is represented in the general population or the population of those with the disease. 

In 2015, Welch, et. al. proposed the development of an extension to the Consolidated Standards of Reporting Trials (CONSORT) guideline to improve the reporting of health equity.⁴⁰ This CONSORT-equity extension (CONSORT-Equity 2017) was developed in 2017 using the place of residence, race/ethnicity/culture/language, occupation, sex/gender, religion, education, socioeconomic status, social capital, and “plus,” that includes other context specific factors (PROGRESS-Plus) framework.^41-43 The team further evaluated the CONSORT equity extension by applying it to 200 randomly selected health equity-relevant trials published from 2013-2015 and found that reporting ranged by characteristic from rare (sexual orientation: 3%) to quite high (for personal characteristics, including age: 96%). Sex was reported in approximately three-quarters of the trials and race in approximately two-thirds.⁴⁴ Although this CONSORT-equity extension was proposed in 2017, it has not yet been required by journals, as was proposed by Welch, et. al.⁴³

Policies to Increase Access to Novel, Effective Treatments

Equity does not end when the trial is complete. We must provide access to the drugs and devices after trials are complete and have demonstrated the treatments to be effective. Individuals from groups that are underrepresented or have been minoritized are disproportionately burdened, yet they ultimately reap fewer benefits or are less likely to have access to the newly developed therapies and treatments once brought to market. Evidence suggests that the use of innovative and/or expensive medical therapeutics is uneven across patient groups.^45,46 More recent studies of high-cost oncology drugs reported that patients from groups that are racially or ethnically minoritized were less likely to use those drugs than other patients.^47,48 Implicit bias among health care professionals may also be a contributing factor. Implicit bias can influence clinical decision making,⁴⁹ for example, resulting in delays in diagnosis and lower prescribing rates of certain medications to some patient groups based on stereotypes or assumptions made by providers. This has been a significant contributor to the historical mistrust that has developed over decades and even centuries of abuse. 

It is estimated that nearly 1 in 4 individuals in the US who take prescription drugs face challenges in affording their medications.⁵⁰ According to a recent report by the American Association of Retired Persons (AARP), prices for 180 widely used specialty prescription drugs increased by an average of 4.8% in 2020, compared with 1.3% in 2019.⁵¹ There are many examples of high drug costs for treatment of serious illnesses that disproportionately affect communities of color. One such treatment, sofosbuvir, is a drug with an estimated 90% cure rate for hepatitis C virus (HCV) infection^52-54, an illness that affects Black and Native American individuals at roughly twice the rate of non-Hispanic White individuals in the US.⁵⁵ Despite sofosbuvir being listed on the World Health Organization Model List of Essential Medicines,⁵⁶ health plans routinely deny coverage due to its cost: $64,693 for a 12-week treatment in 2020.^57-60 Although sofosbuvir could be cost effective, given that it prevents the ultimate need for a liver transplant, the financial impact is prohibitive for US insurance companies to make it available for all patients with HCV infections.⁶⁰ Unfortunately, Black and Native American individuals are more likely to be uninsured or have public insurance coverage⁶¹, and, despite being more likely to need the drug, they are less likely to receive this life-saving medication.

Rising drug prices are often justified by the estimated costs required to develop, test, and eventually bring new drugs and therapeutic agents to market. Based on data for 63 new therapeutic agents (out of 355 approved by the FDA) developed by 47 companies between 2009 and 2018, the median research and development investment required to bring a new drug to market was estimated to be $985 million.⁶² The analysis accounted for costs of failed clinical trials and varied in sensitivity analyses using different estimates of trial success, preclinical expenditures, and cost of capital.⁶² In a series of studies in 1991, 2003, and 2016, DiMasi and colleagues considered randomly selected new drugs from 10 pharmaceutical companies. The studies determined that the costs to develop these new compounds increased from 1987 to 2000 to 2013 at rates well above those of inflation, and, as of 2013, the cost to develop a single new compound was estimated at $1.4 billion.^63-65 While there is truth to the justification of these expenses, the current societal framework disallows for equity in access to these treatments as the high costs may be pushed to patients, making treatment and benefit from novel treatments an impossibility. 

An interesting example—and societal dilemma—is the two treatments for gastrointestinal stromal tumors (GIST), each costing approximately $1000/day, ~$30K for a 1-month supply.⁶⁶  While the overall incidence rate for GIST is estimated to be 7.5 per 1 million, the incidence rate is twice as high for Black individuals as for non-Hispanic White individuals.⁶⁷ Given existing and previously documented race/ethnic disparities in access to novel treatments, this underscores the need to ensure diversity in clinical trial participants as new therapies are tested. Further, adults with Medicaid insurance or no insurance have been found to have higher odds of metastases at diagnosis of soft-tissue sarcomas such as GIST, compared to those with insurance.⁶⁸ While manufacturers of both drugs offer financial assistance programs and aid for those who are unable to afford treatment, patient assistance programs, in general, can be extremely challenging to navigate, especially for individuals who are in crisis, may have limited social support, or may have lower health literacy.  The programs put the onus on the patient to act, whereas a more proactive approach, with case management support, may be warranted for individuals in these populations.^69-71 Evidence continues to emerge on the impact and effectiveness of these programs for improving access for those who need it most.^69-72 As we increase efforts to engage individuals from underrepresented and potentially underserved communities, there must be increased scrutiny and upfront consideration to ensure access to the medications, regardless of financial status or other sociodemographic characteristics. Additionally, we may need to consider outreach through an equity lens rather than an equality lens, offering disproportionate assistance to those in need. 

Conclusion

The disparities that were evident in morbidity and mortality associated with COVID-19 serve as a striking example of how longstanding inequities among people from populations that have been racially, socially, and economically minoritized and marginalized can become exacerbated, widening the gaps.^4,5 Health equity pertaining to access to novel treatments and devices is vital across all stages of the innovation cycle, from clinical trial to broad dissemination. To achieve equity in health outcomes, we must also achieve equity in clinical research. We must collaborate across different types of institutions and funders to work toward a shared goal — to increase access to trials, increase engagement among people from underrepresented groups, implement metrics to promote equitable inclusion and transparency, and finally implement policies to facilitate access after the successful treatments are brought to market. As health care researchers, we have an opportunity to study these disparities and work together to develop, implement, and evaluate solutions to promote health equity for all.  

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Author Information

Authors: Alice PressmanPhD, MS^1,2; Kristen MJ Azar, RN, MSN, MPH, FAHA^2,3
Affiliations: ¹PRECISIONheor, Boston MA, ²University of California, San Francisco, Department of Epidemiology and Biostatistics; ³Sutter Health Institute for Advancing Health Equity, Sacramento CA
Disclosures: The authors have no disclosures to report