Clinical Trials In Crisis: Building On COVID-19’s Lessons Toward A Better Future


Editor’s Note

This post is part of the Health Affairs Blog short series, “Envisioning A Transformed Clinical Trials Enterprise For 2030.” The series explores ideas for advancing a clinical trials enterprise that is more efficient, effective, person-centered, inclusive, and integrated into the health delivery system of 2030 than is currently the case. The series is being published in conjunction with a four-part public workshop, Envisioning a Transformed Clinical Trials Enterprise in 2030, convened under the auspices of the National Academies Forum on Drug Discovery, Development, and Translation. Posts in this series are published by Health Affairs Blog with the support of the National Academies, but they represent the opinions of the authors and do not necessarily represent the views of the Forum on Drug Discovery, Development, and Translation, the National Academies, or any other organization; these posts do not constitute reports or products of the National Academies.

The US clinical trials enterprise reflects our health care system: fragmented, expensive, and unnecessarily complex. The US ranks lowest in health care outcomes among high-income countries despite spending the most as a percentage of gross domestic product. Similarly, public and private spending and investment in biomedical research is higher in the US than in other countries, yet—as the COVID-19 pandemic laid bare—our clinical trials ecosystem is inefficient and siloed and fails at critical moments.

Janet Woodcock, MD, acting commissioner of the Food and Drug Administration (FDA), notes that only five percent of clinical trial arms for COVID-19 therapies will yield generalizable information on safety and efficacy, given low enrollment and lack of trial-design focus on assessment of clinical benefits and risks. The fragmentation in funding and study priorities from industry, academia, and investigator-initiated studies, exacerbated by market forces, leads us to the question: Are US clinical trials asking the right questions to address the greatest public health needs plaguing the nation?

Furthermore, we fail to broadly engage the public or patients in clinical trials. Broad participation in clinical trials moves science toward better treatments for different populations and subgroups. Yet, the vast majority of trials occur in academic research centers or professional research sites funded by industry. Few clinical trial networks exist in community-based settings where the majority of patients receive care. For example, only 8 percent of adult cancer patients participate in clinical trials—despite the prevalence of cancer in the US, along with other chronic conditions such as heart disease, chronic lung disease, stroke, mental health conditions, and diabetes. These conditions rank high in the leading causes of death and disability and serve as a key driver of health care costs. Although, we have had recent progress in medical research investment in rare diseases, more opportunities to expand patient participation in clinical trials are needed, and the economic burden of these diseases is still too high.

Representation in clinical trials similarly poses a challenge. The race distribution of new drug trials provided in the FDA 2015–-2019 summary report showed 7 percent Black/African American and 13 percent Hispanic participation across that period. While some minority participation does occur, true engagement will require significant change in the location and orientation of clinical research.  

In addition, our clinical trials are becoming increasingly and unnecessarily complex. Patients must often meet rigid inclusion and exclusion criteria, limiting the number of patients who can participate and resulting in longer times for trials to meet enrollment targets. While these criteria may increase the chances of optimizing the benefit and risk balance in the trial, they may also limit the generalizability of the results, eventually leading to inadequate evidence and poorly targeted treatment. Existing infrastructure creates high barriers to entry for new trial sites. New sites require significant investment in resources such as workforce training and clinical trials data systems that are not well integrated into existing health data platforms. Community sites are not incentivized with appropriate levels of reimbursement to participate.

In this sea of challenges, opportunities for fundamental change have emerged. This year was a time for reflection on changes made to the clinical trials enterprise in response to the COVID-19 pandemic and for more purposefully considering how the system ought to be redesigned. The National Academies Forum on Drug Discovery, Development, and Translation convened a multipart public workshop Envisioning a Transformed Clinical Trials Enterprise for 2030. These events offered the opportunity to reflect on lessons learned over the past 10 years and experiences during the pandemic. As participants in workshop and breakout group discussions, we noticed three major themes emerge as categories for improvement—engagement, efficiency, and coordination—and one resounding call to action: We must not let this crisis go to waste.

Engagement

If we hope to engage people from communities typically underrepresented in (or, to be more historically accurate, at times abused and neglected by) biomedical research, then we have to reach further upstream to ask if we are doing research that will benefit those communities. Framing research with questions such as, “How can I do research that matters to you?” rather than, “How can you help me do research that matters to researchers?” is the only way to meaningfully build trust with communities and community practitioners.

It is more important than ever, as we are directly confronted with the inequity in our health care system, to improve the diversity of clinical trial participants through meaningful engagement rather than just “recruitment.” Trials in the future should reflect the burden of disease, including both prevalent and rare diseases, and focus on engaging participants from—and improving trial relevance to—underrepresented groups.

Diversity and inclusivity must be defined broadly if clinical trials are to better help all people. Diverse racial and ethnic groups, pregnant and lactating women, older adults, rural populations, populations hesitant with or unable to access technologies, and others must be involved in decision making and defining research that is important and helpful to them.

Patients should be involved at every point of clinical trial design. Researchers and all participants in the clinical trials enterprise need to conduct more outreach and ongoing communication, and to make local, community education a regular part of health literacy. The Patient-Centered Outcomes Research Institute offers unique approaches to patient engagement in research that could be expanded. Approaches to building a more person-centered, easily accessible, diverse, and equitable clinical trials enterprise include

  • enhancing community engagement, “user-friendliness,” and relevance of trials from early target identification through the conduct of trials;
  • extending the reach, reliability, and reportability of clinical trials;
  • developing processes and decision-making tools for patients and clinicians to better assess opportunities to participate in clinical trials;
  • bridging the technical divide;
  • lowering barriers to recruitment so that participating in clinical trials is a straightforward option for patients, the clinicians with whom they interact, and the provider organizations that often serve as gatekeepers;
  • enabling community-based clinicians and provider organizations in rural or underserved areas to participate;
  • explicitly acknowledging historical neglect or injustice; and
  • engaging a more diverse clinical trials workforce at all levels—including leadership.

Efficiency

The clinical trials enterprise should pare away components that cost money and time without either adding scientific value or protecting research participants. Wasted funding and time is a burden on all. Simpler, more pragmatic trials showed their value during COVID-19. The RECOVERY Trial in the United Kingdom, for example, benefited from a clinical research network embedded within the National Health Service that quickly enabled deployment of a randomized control trial protocol across all hospital systems within the system, allowing thousands of patients to participate across various health settings, including community hospitals. Master protocols and adaptive trial designs through the National Institutes of Health Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public-private partnership led to answers on effective treatments such as monoclonal antibodies. Operation Warp Speed directed national priorities and alignment on clinical trial protocols for COVID-19 vaccine trials and placed big bets that led to several vaccines obtaining emergency use authorization in record time.

Technology also showed its value during the pandemic by helping increase participation or maintain enrollment in existing trials. Remote monitoring enabled data collection and lab reporting, supporting a move toward a new “standard” hybrid model between in-person and decentralized trials. Application of new technologies to clinical research should aim to transform trial operations rather than replicate traditional processes.

There are several approaches that can simplify trials and lower costs while still generating high-quality data and robust answers to relevant research questions. These include streamlining trial startup and enrollment processes; simplifying contracting, institutional review board review, and startup costs and training for community-based local sites or sites not supported by National Institutes of Health resources to enable them to participate; simplifying or standardizing data collection from multiple sources (for example, smartphone apps, wearable sensors) to enable broader data sharing and data use/reuse; enhancing the role of routine data capture to minimize patient and clinician burden; enabling data, information, and knowledge exchange among key stakeholders (for example, building federated networks of real-world data to optimize clinical trial operations); and clarifying rules governing the use of technology in clinical trials and establishing the appropriate balance between patient protections and industry opportunities.

Coordination

As we move to a new future, a community-based clinical trials enterprise and a clinical research focus beyond academic sites are foundational. Academic incentives, enabled by funders, may encourage publication quantity over public interest in research prioritization, discourage innovative collaborations, and keep studies concentrated in the same academic centers that have traditionally hosted them, further impeding community involvement. A new vision for a national clinical trials network that serves national public health priorities requires a cohesive plan with a central entity to oversee massive shifts in the current system.

Ensuring optimal use of limited resources (funding and time) and people (participants and clinical staff) requires re-alignment of incentives toward public health outcomes and a governance structure capable of prioritizing research with the greatest public health benefit. Increasing science education for the public, to improve trust in science, could facilitate this realignment. Improving patient diversity requires building a diverse clinical trials workforce. At the same time, the existing workforce could be leveraged more effectively, and new types of workforce capabilities could be built to answer the growing and changing needs of the clinical trials enterprise.

Promising approaches to establishing a network of community-based clinical trial sites include creating a mechanism to enable more efficient information sharing, among community-based stakeholders and others, in trial design, conduct, and analyses; developing process or decision-making tool(s) to assist in prioritizing resources and identifying unnecessary duplication or fragmentation; enabling sustained, reciprocal, multistakeholder community-based partnerships that support cooperation and mutual learning throughout the research and development lifecycle; and establishing infrastructure and training opportunities to support an effective and prepared clinical trials workforce in rural and underserved community locations.

Toward A National Network Of Clinical Trials In Community Practice

Early on in the process, research should be exploratory, innovative, and pursue broad options. But the concept of a national-level network means that limited national resources should be directed toward well-designed studies with significant public health implications that are likely to result in actionable evidence. What entity should be the one to prioritize studies? If it is a new entity, what should it look like? Where should funding and support for this entity come from? An interesting idea comes from RECOVERY and ACTIV in curating priorities for research. In each of these initiatives, a separate advisory committee makes decisions on what research questions are prioritized, which networks are engaged to answer those questions, and what resources are deployed to those trials.

Concrete goals and metrics can help assign a direction to systemic changes and measure progress. The FDA has made some progress in developing metrics to track diversity and inclusion in clinical trials, but we can do more and do better. What should additional metrics look like, and who should track them to measure progress?

The system is fundamentally fragmented, but the COVID-19 pandemic taught us that we have the vision for the way forward. We need leadership and focus to align the system toward shared goals. The shared leadership must include government and private funders, regulators, academics, community and public health leaders, and nonprofit groups dedicated to reducing disparities and increasing access to high-quality, evidenced-based health care. Even as the pandemic wanes in the US, we must capitalize on the shared sense of mission and research focus that the pandemic engendered.

Authors’ Note

The authors thank the staff of the National Academies, including L. Shern, C. Shore, A. Wagner Gee, and A. March, for contributing to the development of this blog post.

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