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Introduction and Highlights of the Workshop¹

Even as the U.S. population becomes steadily more diverse, minorities and women remain underrepresented in clinical trials to develop new drugs and medical devices. Although progress in increasing minority participation in clinical trials has occurred, “Participation rates do not fully represent the overall population of minorities in the United States” (Fisher and Kalbaugh, 2011, p. 2217). This underrepresentation threatens the health of both these populations and the general population, since greater minority representation could reveal factors that affect health in all populations. Federal legislation has sought to increase the representation of minorities and women in clinical trials,² but legislation by itself has not been sufficient to overcome the many barriers to greater participation. Only much broader changes will bring about the meaningful participation of all population groups in the clinical research needed to improve health. For example, careful attention to the U.S. Food and Drug Administration’s (FDA’s) Action Plan to Enhance the Collection and Availability of Demographic Subgroup Data (2014) can be used as a guide to these efforts.

To examine the barriers to participation in clinical trials and ways of overcoming those barriers, the Roundtable on the Promotion of Health

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¹ The planning committee’s role was limited to planning the workshop, and this Proceedings of a Workshop has been prepared by the rapporteurs as a factual account of what occurred at the workshop. Statements, recommendations, and opinions expressed are those of the individual presenters and participants and are not necessarily endorsed or verified by the National Academies of Sciences, Engineering, and Medicine. They should not be construed as reflecting any group consensus.

² Specifically, the NIH Revitalization Act of 1993.

Equity and the Elimination of Health Disparities (see Box 1-1) held a workshop in Washington, DC, on April 9, 2015, titled “Strategies for Ensuring Diversity, Inclusion, and Meaningful Participation in Clinical Trials.” As Toni Villarruel, Margaret Bond Simon Dean of Nursing at the University of Pennsylvania School of Nursing, said in her introductory remarks at the workshop, the underrepresentation of minorities in clinical trials has been a persistent problem, but the dialogue to prepare for the workshop left the planning committee “energized.” She pointed out that the workshop was to look at how the clinical trial process can better address subgroup differences. However, there is a balance between separating out groups and achieving numbers that are meaningful. One question is whether more race-specific trials are needed. A broader question is whether sufficient numbers of patients participate in a trial and how to put all the pieces together to drive better clinical outcomes. Answering these questions and increasing representation require a multistakeholder engagement, she said, which accounted for the breadth of institutional expertise represented at the workshop.

HEALTH DISPARITIES AND CLINICAL TRIALS

In his introductory remarks at the workshop, National Academy of Medicine President Victor Dzau said, “The issue of eliminating health disparities is essential to our society, to all of us, and certainly to me.” Dzau was born in postwar China, where he observed poverty and disparities firsthand, and he has worked extensively on disparities issues as a researcher and administrator at Duke University. “The health field is not just about health care,” he said. “It is about strengthening everything about health, which means, of course, addressing many social issues.” In that context,

“Understanding and addressing the root cause of health disparities is what we must all do.”

Despite the great advances of science and technology in medicine in recent years, inequities are still prominent in the United States and globally. The National Academy of Medicine has a responsibility, said Dzau, to discuss how to change this. As such, the work of the roundtable is a thread that runs through all the work being done by the Academies.

Barriers to meaningful participation in clinical trials include language differences, cultural differences, and a history of discrimination and exploitation, Dzau said, adding that “We all need to do better.” The scientific community does not have all the tools it needs, but that is why the Academies bring the best minds together to discuss the problems and arrive at innovative ways to address those problems. “I know that you will showcase some of those innovative approaches today at this meeting,” he concluded.

ORIGINS OF THE WORKSHOP

The workshop was the continuation of a historical process, said Jonca Bull, director of the Office of Minority Health at FDA, in her introductory presentation at the workshop. Thirty years ago, the Heckler Report documented the existence of health disparities among racial and ethnic minorities in the United States and called such disparities “an affront both to our ideals and to the ongoing genius of American medicine” (Task Force on Black and Minority Health, 1985). In 2003 the Institute of Medicine (IOM) report Unequal Treatment: Confronting Racial and Ethnic Disparities in Health Care began with the words, “Racial and ethnic minorities tend to receive a lower quality of health care than nonminorities, even when access-related factors, such as patients’ insurance status and income, are controlled” (IOM, 2003, p. 1).

In 2012, legislation that reauthorized FDA user fees,³ which are essential for agency operations, included provisions under Section 907 requiring that FDA publicly report data on the inclusion and analysis of women in FDA applications, with additional provisions in legislation requiring the same for race and ethnicity. This legislation mandated that, within 1 year of enactment, FDA would provide to Congress and post on the FDA website a report on the extent of clinical trial participation and on the quality of analyses to determine safety and effectiveness for demographic subgroups included in applications submitted to FDA, while taking into account FDA

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³ The FDA Safety and Innovation Act of 2012, although primarily focused on the reauthorization of user fees for pharmaceutical companies, also contained a provision, Section 907, that directs these companies to improve demographic subgroup data’s completeness, quality, and availability.

regulations and requirements for protecting the confidential commercial information of sponsors.

This legislation led to an action plan designed to address deficiencies that also reflected several concerns expressed in an April 30, 2014, letter to FDA from Senator Debbie Stabenow. This letter asked FDA to require representative proportions of women and minorities in industry-sponsored clinical trials comparable to that of the National Institutes of Health (NIH). It asked about the specific actions that FDA would take, in cooperation with industry, to achieve meaningful subgroup analyses for safety and efficacy, clear timelines for enforcement that do not necessarily disrupt trials, and the provision of transparent and publicly available results. The letter also asked FDA to publicly and regularly report progress implementing the action plan and to identify when further action is needed.⁴

The action plan has three overarching priorities (FDA, 2014):

• Improve the completeness and quality of demographic subgroup data collection, reporting, and analysis.
• Identify barriers to subgroup enrollment in clinical trials, and employ strategies to encourage greater participation.
• Make demographic subgroup data more available and transparent.

As an example of the work being done under the plan, Bull cited changes to the MedWatch Form, which collects spontaneous adverse event reports after a product goes to market. The next update of the form will include demographic data beyond just male and female, which will mark “a major step forward for us and for the postmarketing environment,” said Bull. She also mentioned the Drug Trials Snapshot, which provides information about the sex, age, race, and ethnicity of clinical trial participants for recently approved drugs. With one drug in the snapshot, women represented only 24 percent of participants, and more than 87 percent of the participants were white. With another drug used to treat multiple myeloma, a disease that differs among population groups, only 3 percent of participants were African Americans.

FDA’s policies have been evolving since the development of the action plan and will take time to be implemented, said Bull. But FDA policy now explicitly states “The database submitted in a marketing application should reflect usage in a diverse racial population, one reflective of the likely patient mix postmarketing, for potential differences in response to become apparent.” The challenge, said Bull, is to implement this policy and execute it well.

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⁴ An FDA website provides updates of the agency’s activities related to Section 907 of the legislation: http://www.fda.gov/RegulatoryInformation/Legislation/SignificantAmendmentstotheFDCAct/FDASIA/ucm389100.htm (accessed July 1, 2015).

In a 2014 speech, FDA Commissioner Margaret Hamburg said:

Bull concluded with several questions to be kept in mind during the workshop:

• How can health disparities be measured, and what should be measured? Classifications of participants often are not consistent with the definitions of race and ethnicity established elsewhere in the federal government and also must take into account that data are often being generated globally. The constructs of race, ethnicity, and gender continue to generate questions and controversy.
• What is meaningful participation in the context of clinical trial design? Estimating the treatment effect within a group or the heterogeneity of treatment effect across groups is critical, which raises the question of which drugs or other medical products need to be identified early for special consideration for subgroups.
• What steps can FDA and NIH take in working together with academia and industry to ensure the meaningful participation of diverse groups in clinical trials?

HIGHLIGHTS OF THE WORKSHOP

During the concluding session and at several other points during the workshop, the workshop speakers and participants pointed to important messages that emerged from the presentations and discussions. These messages are summarized here as an introduction to the main ideas of the workshop. They should not be seen as a consensus of workshop participants or as the conclusions of the workshop as a whole.

• Progress in science and medicine requires that patients participate in clinical trials (Brooks, Buch).

• The motivations to participate in clinical trials have as much or more to do with context, including family and community, as with potential benefits to the participant (Horowitz, Solomon, C. Ulrich).
• Barriers to participation in clinical trials include mistrust, costs, language and cultural differences, lack of awareness of trials, and trial designs that tend to exclude minorities (Hickam, J. Ulrich).
• Despite these barriers, when given the opportunity, minorities are just as likely to participate in clinical trials as the majority population (Brawley, Ramirez).
• Perceptions and messaging are critical factors in decisions about whether to participate in a clinical trial (Buch, Horowitz, Solomon, C. Ulrich).
• The foundation of participation in a clinical trial is trust, whether in a health care provider, a research, a funder, or a government (Chen, Dzau, Ellen, Horowitz, Kim, Ramirez, Solomon, C. Ulrich).
• Minorities underrepresented in clinical research are heterogeneous, which requires creative and intellectually rigorous ways of collecting information from groups that may be hard to reach (Ellen, Horowitz).
• The categories used to collect information about race and ethnicity, which were developed by government for administrative purposes, create difficulties when applied to clinical research (Brawley, Rotimi, J. Ulrich).
• Federal agencies are both mandated and committed to increasing the representation of minorities in clinical trials (Buch, Bull, J. Ulrich).
• The recruitment and retention of participants in clinical trials are multifaceted problems that involve funders, researchers, health care providers, patients, advocacy groups, and the public interest (C. Ulrich).
• Incentives can influence the decisions of researchers and health care providers, as with incentives encouraging physicians to practice in particular places (Brooks).
• However, social change is slow, and incentives can take a long time to have an effect (Brooks, Buch).
• Engaging communities not as subjects but as partners in research can not only increase participation but change the nature of clinical trials (Brooks, Ellen, Hickam, Horowitz, Kim, Ramirez, Solomon, C. Ulrich).
• Greater minority representation among research leaders and research teams can boost the participation of underrepresented minorities in clinical trials (Brooks).

• New technologies such as apps on smartphones could both explain clinical trials more simply and clearly and improve recruitment into trials (Ellen, Kim, J. Ulrich).
• Basic questions such as how much information is required to ensure safety and efficacy in subgroups still have not been completely answered (Buch, Bull, Dzau).
• The emerging era of personalized medicine, in which people are treated on the basis of their individual genetic sequences and experiences, will raise fundamental questions about how to ensure diversity in clinical trials (Buch).

ORGANIZATION OF THE PROCEEDINGS OF A WORKSHOP

Following this introductory chapter, Chapter 2 provides a historical perspective on both racial and ethnic differences in human population and on the representation of minorities and women in clinical trials.

Chapter 3 examines some of the scientific issues that arise in efforts to achieve clinically meaningful inclusion, such as the size of the subgroups needed to produce useful results and how best to involve communities in scientific research.

Chapter 4 looks at some of the barriers to participation posed by health care providers, institutions, and systems, such as the difficulties in achieving informed consent and the mistrust created by historical abuses.

Finally, Chapter 5 considers potential best practices and policy options to increase the recruitment and retention of minorities and women in clinical trials, with a final list of potential best practices drawn from the presentations summarized in that chapter.

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