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Recommendations for Improving Representation in Clinical Trials and Clinical Research

CONCLUSIONS

1. Improving representation in clinical research is urgent.

   The scientific necessity to improve research equity is urgent. The United States is becoming more diverse, with the 2020 U.S. Census finding that the number of people who identify as white has decreased for the first time since a census started being taken in 1790. Despite greater diversity, deep disparities in health are persistent, pervasive, and costly. Without major advancements in the inclusion of underrepresented and excluded populations in health research, meaningful reductions in disparities in chronic diseases such as diabetes, cancer, and Alzheimer’s disease remain unlikely. Purposeful and deliberate change is needed. As the United States becomes more diverse every day, failing to reach these growing communities will only prove more costly over time (see Chapter 2).

2. Improving representation in clinical research requires investment.

   Improving the representation of underrepresented and excluded populations in clinical trials and clinical research requires a substantial investment of time, money, and effort. Investment of time and resources are needed to build and restore trust with underrepresented and excluded communities. Building trust with local communities cannot be episodic or transactional and pursued only to meet the goals of specific studies; it requires sustained presence, commitment, and investment. Investments are also needed in the systems and technologies that reduce burdens to participation by underrepresented and excluded populations, such as by adequately compensating participants financially for their time when participating in research and by investing resources in making participation

2. more physically accessible. Lastly, we need to invest in creating a more diverse workforce that better reflects the diversity of our country. This not only has implications for study-site personnel and their direct interactions with participants, but also influences the types of research questions that get asked, the types of research that gets funded, and even the types of research that are published. To better address health disparities and ensure health equity for all, the U.S. workforce should look more like the nation (see Chapter 4).

3. Improving representation requires transparency and accountability.

   Transparency and accountability throughout the entire research enterprise will be critical to driving change and must be present at all points in the research life cycle—from the questions being addressed, to ensuring the populations most affected by the health problems are engaged and considered in the design of the study, to recruitment and retention of study participants, to analysis and reporting of results. Individual investigators and research institutions on the front lines bear responsibility for transparency in reporting progress toward the goals of inclusion in research, but this must be reinforced by transparency and accountability that funding agencies and industry sponsors have across their portfolios, that regulatory agencies have in their role governing the conduct of research as well as the approval and reimbursement of the drugs and devices that are often the final products of clinical research, and that journal editors and others that disseminate research have in communicating findings (see Chapters 3, 4, and 5).

4. Improving representation in clinical research is the responsibility of everyone involved in the clinical research enterprise.

   The clinical research landscape is complex and involves multiple stakeholders—participants, communities, investigators, institutional review boards, industry sponsors, institutions, funders, regulators, journals, and policy makers. Each of these stakeholders has a critical role to play in achieving the goal of improving representation in clinical research, but the complex nature of the research ecosystem and research processes, combined with lack of accountability and historic underinvestment means that an issue that should be everyone’s responsibility can become no one’s priority. In this report, the committee emphasizes that the research supports taking a systematic approach to addressing this issue; one in which all stakeholders take responsibility for the important role they can play in supporting representation in clinical research participation.

   The committee was asked, “Who bears the cost of more inclusive science?” The responsibility (and therefore the cost) will be borne to some extent by all stakeholders in the larger research ecosystem, acting in concert to achieve this larger societal and scientific goal. Those that profit from scientific discovery bear particular responsibility in shouldering the

4. cost of inclusivity. The federal government has a notably prominent role and responsibility in achieving the goal of more inclusive research, as a primary funder of the research enterprise with taxpayer dollars, regulator of the processes of scientific research, gatekeeper to approvals for monetizing scientific discovery, and purchaser of new drugs and devices. More coherence of federal policy to align investment and accountability to achieve the goals of inclusive science is warranted.

   In answering the question of who bears the cost of more inclusive science, we must also ask, “Who bears the cost of the current lack of inclusivity?” That cost is large (as evidenced by the analysis in Chapter 2), is borne disproportionately by underrepresented and historically excluded communities, but saps the health and economic strength of the entire society.

5. Creating a more equitable future entails a paradigm shift.

   The committee sees the need for both pragmatic approaches and an aspirational vision. To realize a more equitable future, the report epilogue implores the field to embrace a paradigm shift that moves the balance of power from institutions and puts at the center the priorities, interests, and voices of the community. An ideal clinical trial and clinical research enterprise pursues justice in the science of inclusion through scalable frameworks; expects transparency and accountability; invests more in people, institutions, and communities to drive equity; and invests in the science of community engagement and empowerment. These ideals should be the foundation of the actions that stakeholders take to make sustainable change.

RECOMMENDATIONS

The committee’s recommendations focus on tangible actions that must urgently be taken within the context of the existing structures of the clinical research ecosystem in order to achieve the goals of representation and inclusion. Although individual researchers can take many actions to improve equity in clinical trials and clinical research, as described in Chapter 5, the committee focused on system-level recommendations to drive change on a broader scale. The committee presents 17 recommendations to improve the representation of underrepresented and excluded populations in clinical trials and clinical research and create lasting change.

The urgency of addressing the equity in research participation and the lack of substantial progress despite stated commitments led the committee to propose bold recommendations with potentially far-reaching implications. The committee is aware that the complexity of the U.S. health-care system poses significant challenges to transforming the clinical research system, and these systematic challenges will also influence the implementation of the committee’s recommen-

dations. While providing a complete policy assessment for each recommendation was outside of the committee’s scope and charge, the committee does not deny that there will be costs—both fiscal and political—associated with the implementation of the recommendations. These costs must be carefully weighed against the potential for long-term benefit. Changing our nation’s approach to clinical research may require significant upfront costs to more equitably recruit and retain a diverse group of participants and to hold investigators accountable when they do not meet these goals. In addition, it will require incentivizing sponsors of clinical research to change the status quo. However, based on the committee’s expert opinion and the available evidence, the committee believes that implementation of its recommendations is necessary to truly drive significant and sustained change to the clinical research system.

Reporting and Accountability

1. The Department of Health and Human Services (HHS) should establish an intradepartmental task force on research equity charged with coordinating data collection and developing better accrual tracking systems across federal agencies, including the Food and Drug Administration (FDA), National Institutes of Health (NIH), Centers for Disease Control and Prevention (CDC), Agency for Healthcare Research and Quality (AHRQ), Health Resources Services Administration (HRSA), Indian Health Services (IHS), Centers for Medicare & Medicaid Services (CMS), and two departments outside the Department of HHS, the Department of Veterans Affairs and Department of Defense. This task force should be charged with the following:
   1. Producing an annual report to Congress on the status of clinical trial and clinical research enrollment in the United States, including the number of patients recruited into clinical studies by phase and condition; their age, sex, gender, race, ethnicity, and trial location (i.e., where participants are recruited); their representativeness of the conditions under investigation; and the research sponsors.
   2. Making data more accessible and transparent throughout the year, such as through a data dashboard that is updated in real time.
   3. Determining what “representativeness” means for protocols and product development plans.
   4. Developing explicit guidance on equitable compensation to research participants and their caregivers, including differential compensation for those who will bear a financial burden to participate.
2. The FDA should require study sponsors to submit a detailed recruitment plan no later than at the time of Investigational New Drug and Investigational Device Exemption application submission that explains how they will ensure that the trial population appropriately

2. reflects the demographics of the disease or condition under study and that provides a justification if these enrollment targets do not match the demographics of the intended patient population in the United States.
3. The NIH should standardize the submission of demographic characteristics for trials to ClinicalTrials.gov beyond existing guidelines so that trial characteristics are labeled uniformly across the database and can be easily disaggregated, exported, and analyzed by the public. The data reported should include the number of patients; their age, sex, gender, race, ethnicity, and trial location (i.e., where participants are recruited); who sponsors them; and language accessibility.
4. In grant proposal review, the NIH should formally incorporate considerations of participant representativeness in the score-driving criteria that assess the scientific integrity and overall impact of a grant proposal. These criteria should be part of the assessment of the scientific approach, including whether it is appropriate for generating insights for the populations to whom the results are intended to generalize. The criteria should also be incorporated in the assessment of whether investigative teams and environment have detailed and feasible plans to meet the goals of representative study enrollment. Additionally, the NIH should assess in its annual review of progress reports of funded studies whether a given study has met the proposed enrollment goals of representativeness by race/ethnicity, sex, and gender, and should establish a plan for remediation for the investigator and/or organization that includes criteria for putting funding on hold that has not met predefined recruitment goals.
5. Journal editors, publishers, and the International Committee on Medical Journal Editors should require information on the representativeness of trials and studies for submissions to their journals, particularly relative to the affected population; should consider this information in accepting submissions; and should publish this information for accepted manuscripts. The information required should include the following:
   1. The disease, problem, or condition under investigation
   2. Special considerations related to sex and gender, age, race or ethnic group, and geography
   3. The overall representativeness of the trial, including how well the study population aligns with the target population in which the results are intended to generalize. If the study population does not align with the population affected by the disease, authors should provide scientific justification for why this is the case.
6. The Office of Human Research Protections (OHRP) and the FDA should direct local institutional review boards (IRBs) to assess and re

6. port the representativeness of clinical trials as one measure of sound research design that it requires for the protection of human subjects. Representativeness should be measured by comparing planned trial enrollment to disease prevalence by sex, age, race, and ethnicity in the trial location (i.e., where participants are recruited). Protocols in which the planned enrollment diverges substantially from disease prevalence should require justification. The OHRP and FDA should establish a plan for remediation for local IRBs that frequently approve protocols that are not representative.
7. The CMS should amend its guidance for coverage with evidence development to require that study protocols include the following:
   1. A plan for recruiting and retaining participants that are representative of the affected beneficiary population in age, race, ethnicity, sex, and gender.
   2. A plan for monitoring achievement of representativeness as described above, and a process for remediation if CED studies are not meeting goals for representativeness.

Federal Incentives

8. In order to determine how to take action on the most effective accountability and incentive structures, Congress should direct the FDA to enforce existing accountability measures, as well as establish a taskforce to study new incentives for new drug and device applications for trials that achieve representative enrollment. Incentive programs should be designed to improve representativeness in clinical research, improve clinical outcomes, and ensure they do not reduce access to new therapies. Some ideas include:
   1. Tax incentives, such as tax credits for research and development
   2. Fast-Track criteria and exemption from some FDA drug application fees
   3. Extended market exclusivity to sponsors who meet predefined criteria of representativeness
   4. Refusing to file an application that does not appropriately represent the target population under study
9. The CMS should expedite coverage decisions for drugs and devices that have been approved based on clinical development programs that are representative of the populations most affected by the treatable condition.
10. The CMS should incentivize community providers to enroll and retain participants in clinical trials by reimbursing for the time and infrastructure that is required. Through the creation of new payment codes, CMS should reimburse activities associated with clinical trial

10. participation, including but not limited to data collection and personnel (e.g., community health workers, patient navigators) to support research education and recruitment.
11. The Government Accountability Office (GAO) should assess the impact of reimbursing routine care costs associated with clinical trial participation for both Medicare (enacted in 2000) and Medicaid (enacted in 2020). The assessment should include an analysis of whether there is timely and complete reimbursement, any implications for innovation and care delivery to underrepresented populations, and any challenges to implementation.

Remuneration

12. Federal regulatory agencies, including the OHRP, NIH, and FDA, should develop explicit guidance to direct local IRBs on equitable compensation to research participants and their caregivers. In recognition that research participation may pose greater hardship or burdens for historically underrepresented groups, the new guidance should encourage and allow for differential compensation to research participants and their caregivers according to the time and financial burdens of their participation. Differential compensation may include additional reimbursement for expenses including but not limited to lost wages for those with lower socioeconomic status (SES), transportation costs, per diem, dependent care, and housing/lodging where applicable.
13. All sponsors of clinical trials and clinical research (e.g., federal, foundation, private and/or industry) should ensure that trials provide adequate compensation for research participants. This compensation may include additional reimbursement for expenses including but not limited to lost wages for lower SES participants and family caregivers, transportation costs, per diem, dependent care, and housing/lodging where applicable.

Education, Workforce, and Partnerships

14. All entities involved in the conduct of clinical trials and clinical research (academic centers, health-care systems, sponsors, regulatory agencies, and industry) should ensure a diverse and inclusive workforce, especially in leadership positions.
15. Leaders and faculty of academic medical centers and large health systems should recognize research and professional efforts to advance community-engaged scholarship and other research to enhance the representativeness of clinical trials as areas of excellence for promotion or tenure.

16. Leaders of academic medical centers and large health systems should provide training in community engagement and in principles of diversity, equity, and inclusion for all study investigators, research grants administration, and IRB staff as a part of the required training for any persons engaging in research involving human subjects. This training should incorporate strategies to enhance diverse recruitment and retention in clinical research, as well as planning of and budgeting for these efforts and timely reimbursement of partnering agencies and organizations.
17. HHS should substantially invest in community research infrastructure that will improve representation in clinical trials and clinical research. This funding should go to agencies such as the HRSA, NIH, AHRQ, CDC, and IHS to expand the capacity of community health centers and safety net hospitals to participate in and initiate clinical research focused on conditions that disproportionately affect the patient populations they serve.