Over the course of the workshop, current and former FDA officials shared their personal perspectives on the current state of the clinical trials enterprise; the unique opportunity to learn from how product development unfolded during the COVID-19 pandemic response; and how to realize the vision of a more efficient, effective, person-centered, and inclusive clinical trials enterprise that is integrated with routine health care delivery.1
OPPORTUNITIES TO TRANSFORM THE CLINICAL TRIALS ENTERPRISE
Mark McClellan, director of the Duke–Margolis Center for Health Policy and former FDA commissioner and former CMS administrator, shared his perspective on opportunities to transform the clinical trials enterprise in a conversation moderated by Amy Abernethy.
Creating More Person-Centered and Accessible Clinical Trials
“There is … broad awareness that we ought to be able to do better,” McClellan said, referring to creating a more person-centered and easily accessible clinical trials enterprise. He referenced the CTTI vision for the clinical trials ecosystem and beyond: transforming clinical trials for 2030,2 which outlines directions for the future (also discussed in Chapter 5).
One approach to increasing patient-centeredness in clinical trials is to integrate trials into routine health care, McClellan said. Integrating data
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1 McClellan and Abernethy spoke at the meeting on May 11, 2021. Janet Woodcock, acting commissioner of food and drugs, FDA, spoke at the meeting on January 26, 2021.
2 For more information, see https://www.ctti-clinicaltrials.org/transforming-trials-2030 (accessed August 3, 2021).
collection and care delivery processes would also align with another key interest of health care organizations: lowering costs. Reimbursement is shifting toward patient-centered, results-based payments (e.g., improving diabetes outcomes) and away from traditional fee-for-service payments, he said. To make this transition, health systems are, for example, investing in medical record integration, developing new team-based approaches to care, and using digital health technologies to remotely monitor patients and support self-management of disease.
The transformation of the clinical trials enterprise continues to move forward during the ongoing response to a pandemic, and McClellan and Abernethy discussed “using the pandemic as a proof point,” learning from what worked and what did not when it comes to simplifying trial designs and integrating clinical research and practice. McClellan pointed to presentations by Martin Landray and others, who described the design and implementation of trials during the pandemic, which enrolled diverse participant populations (e.g., the RECOVERY trial). As another example, he mentioned the NIH Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public–private partnership3 to test new therapeutics and vaccines for effectiveness in treating COVID-19. He described the ACTIV-6 trial4 as “fully distributed” and intentionally designed to be integrated into community-based care. There are positive lessons from those examples on how to efficiently identify and engage potential trial participants, improve the informed consent process, and design trials that are fit-for-purpose and not unnecessarily burdensome for clinicians. Sufficient data will need to be collected to define the safety profile of interventions and characterize patient responses, he said, whether the interventions are new molecular entities or repurposed drug products. Abernethy summarized that clinical trials conducted within the context of clinical care should still provide robust answers to key questions and keep patients safe, all while increasing efficiency overall.
Building Trust and Engaging Communities
Building community trust in the research enterprise and including the patient perspective in the early stages of trial development are “hallmarks” of clinical trials that have been successfully inclusive of diverse populations, McClellan said. He noted that this concept is discussed in the
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3 For more information, see https://www.nih.gov/research-training/medical-researchinitiatives/activ (accessed August 1, 2021).
4 For more information, see https://www.nih.gov/research-training/medical-researchinitiatives/activ/covid-19-therapeutics-prioritized-testing-clinical-trials#activ6 (accessed August 3, 2021).
CTTI vision statement for 20305 as part of building more patient-centered and easily accessible trials.
McClellan observed that some of the early COVID-19 trials recruited participants through existing academic clinical networks and, as a result, did not successfully enroll participants. Abernethy emphasized that trials should “meet people where they are” by making it easier for health systems and the organizations that serve them to participate at trial sites. McClellan discussed two approaches for better engaging patients in the community.
- Simplify existing trial networks. Consider how trial networks could be adapted to reach broader populations using the tools and technologies discussed at the workshop to improve regulatory interactions, IRB oversight, and frontline clinician training. Abernethy described this as “wicking away the work” to reduce the burden for community health care providers who must balance enrolling a patient in a clinical trial against other tasks and payment incentives.
- Leverage capacity outside of the clinical trials enterprise. Capacities for longitudinal patient tracking are already being deployed on the care delivery side. There are “increasingly sophisticated electronic registries powered by payment reforms and performance accountability around improving outcomes,” McClellan explained. Federally qualified health centers, accountable care organizations, and other health organizations that serve more vulnerable communities are using longitudinal patient tracking for quality improvement and for targeting interventions (e.g., identifying patients who might benefit from telehealth services). Additionally, there is a growing base of reliable longitudinal information on characteristics of patients with common chronic diseases, which may include data on characteristics that may not be captured through clinical trials (e.g., housing status, food insecurity), but are relevant for health outcomes.
Facilitating Action Through Government Support and Coordination
A key role for government is to be a facilitator of the actions discussed throughout the workshop, McClellan said. He added that there are opportunities to facilitate change in the clinical trials enterprise by building on ongoing public health policy activities. For example, the
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5 For more information, see https://ctti-clinicaltrials.org/who_we_are/transforming-trials-2030 (accessed April 13, 2022).
reauthorization of PDUFA provides an opportunity for FDA to promote more comprehensive and coordinated data collection. Another opportunity is, as discussed, learning from what did and did not work during the COVID-19 pandemic response, especially around rapidly mobilizing for evidence generation. Federal agencies other than FDA taking action in this area could also include NIH and the Biomedical Advanced Research and Development Authority.
As drug discovery, development, and translation have evolved, pre- and postmarket evidence generation has become more of a continuum, McClellan pointed out. This is related, in part, to FDA’s accelerated product approval pathways for breakthrough treatments that address serious unmet medical needs. But it is also about putting into practice the concept of a learning health care system. He noted that the federal government is interested in policy changes that support the collection of better postmarket data and the translation of that data into health care practice. For example, CMS called for public comment on a new Medicare coverage pathway, Medicare Coverage of Innovative Technology,6 for FDA-designated breakthrough medical devices, and he anticipated this may inform development of new policies related to federal support for registries or other platforms for collecting evidence after marketing approval. McClellan also highlighted the opportunity to update policies that cover advanced diagnostics, including artificial intelligence– and big data–informed diagnostic capabilities. This area could benefit from the ability to leverage real-world evidence and, potentially, to randomize populations for evidence collection in the postmarket setting.
In closing, McClellan emphasized that it is easier for the federal government to act on an issue when there is strong stakeholder support for taking action. Cross-stakeholder consensus and support are needed not only from FDA and research-funding agencies, but also from agencies that engage in and benefit from evidence generation in the postmarket space, such as CMS and The Office of the National Coordinator for Health Information Technology. Abernethy agreed and summarized that “there is a confluence of activity” occurring across federal agencies, but there is a need for support from across the clinical trials stakeholder community.
INNOVATING FOR 2030 NOW
Abernethy offered seven key points to keep in mind as the clinical trials enterprise innovates toward the future. The year “2030 is now,” she
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6 For more information, see https://www.cms.gov/newsroom/fact-sheets/medicare-coverage-innovative-technology-cms-3372-f (accessed August 4, 2021).
said, stressing that the vision for 2030 is unfolding in 2021 and stems from the actions and innovations of today and the coming years.
- Ensuring all stakeholders are at the table. This includes clinical trialists, manufacturers, patients, end users (e.g., quantitative scientists, biostatisticians), technologists, and others. Importantly, Abernethy said, stakeholders need to learn how to talk to each other, as well as how to listen. “How do we make sure that we have all actors at the table, and that we have an equal power dynamic with equal voice?” she asked.
- Including technology experts as partners. Abernethy emphasized that the technology industry should be included in stakeholder discussions as partners, rather than simply as vendors providing services. Technology partners can help envision how the clinical trials enterprise can evolve for the future in terms of technical and data capabilities, she said.
- Ensuring patient-centricity. Clinical trials test new interventions and involve risk for participants. It is important to incorporate patient input and keep patient safety at the forefront of clinical trials, “not in a paternalistic way, but in a way that is a conversation,” Abernethy said. She added that maintaining a focus on participant safety also helps promote trust.
- Remembering the goal of research is generating data. She observed that sometimes there is more attention on the specific technology being used (e.g., telehealth capabilities) rather than the quality of the data being generated. “We need to make sure that the datasets that get generated have the kind of integrity and quality and consistency of data that we are going to need to make confident decisions … about the medical product or health care intervention that is being studied,” Abernethy said. The focus should be on how best to obtain, validate, and use the clinical data that are relevant for the intervention being investigated. For example, trial sponsors, researchers, and regulators could consider whether traceability to source data is needed in specific circumstances, or whether EHR or claims data can be merged with data generated within a clinical trial to build the needed dataset.
- Looking for new and innovative ways to solve problems and develop capabilities for the future. As examples, Abernethy mentioned innovations such as tokenization of health data, privacy-sparing innovations, and synthetic datasets. She added that “new innovations need to be … pressure tested to ensure that the innovation works within our clinical trials ecosystem in a way that continues to ensure patient safety and integrity of the underlying dataset.”
- Ensuring that stakeholders in the clinical trials ecosystem are aware of and understand the new capabilities being deployed. Abernethy emphasized that regulatory agencies, in particular, need to have the opportunity to familiarize themselves with new capabilities being used in clinical trials and to ensure they work as expected and intended within the clinical trials infrastructure. She emphasized that this process of building familiarity builds trust in the new capabilities and infrastructure.
- Focusing on the ultimate goal of informing better health care decisions. The clinical trials infrastructure exists to generate the clinical evidence needed to make decisions about health-related interventions. To be relevant and useful for this task, the clinical trials infrastructure must function as expected; be inclusive to the extent possible; engage stakeholders, including trial participants, in the process; maximize trial participant safety while advancing cutting-edge medical product development; and generate credible, high-quality datasets that can inform decisions and assessments of the medical intervention being studied, Abernethy summarized.
TAKING THE LESSONS FROM THE COVID-19 PANDEMIC RESPONSE FORWARD
Janet Woodcock, acting commissioner of food and drugs, FDA shared her perspective on the current status of the clinical trials ecosystem, discussing the response to the COVID-19 pandemic as a case example, and suggested key actions for moving forward.
Studying the COVID-19 Pandemic Response as a Model
In a public health emergency, such as the COVID-19 pandemic, the goal of the clinical trials enterprise should be to rapidly generate robust, actionable data that can be used to improve standards of care and disease outcomes, Woodcock said. However, the response of the U.S. clinical trials ecosystem to the pandemic was less than optimal. Woodcock reported that more than 500 small therapeutic trials were initiated in the United States, many of which were non-randomized. Only about 5 percent of the trial arms were adequately powered to yield actionable data (i.e., data that are useful to regulators or clinical guideline developers). Many trials were redundant (i.e., numerous small studies testing the same compounds), and many did not achieve rapid or complete enrollment (Bugin and Woodcock, 2021). “In a crisis, we are left with a lot less evidence than we could have had, and that the system could have delivered, had it been
more organized, more focused on the societal goal, and generally more effective,” Woodcock said.
Woodcock suggested that the clinical trials response to the pandemic be studied as a model of the larger clinical trials system in general, which also suffers from barriers to evidence development and clinical evaluation. She noted that discussions of these problems have been ongoing for more than a decade. Still, many remain comfortable with the status quo and there has been little motivation for change. She described the failure to rapidly generate actionable data during the COVID-19 pandemic as “the expected outcome of the system that we have.” What is needed now is an understanding of what contributed to this outcome, followed by efforts to make substantive changes. For example, there are lessons to be learned about site selection from the use of academic medical centers for COVID-19 clinical trials. Woodcock said that conducting clinical research primarily at academic medical centers results in competition for patients, study staff, and other resources, which can slow study progress and limit evidence generation. At the same time, many of those who have the disease being studied receive their health care in other settings and are not afforded the opportunity to participate in, and possibly benefit from, a clinical study.
Building a Community-Based Trials Network
To enable the clinical trials enterprise to be better prepared for the next public health emergency, Woodcock proposed building a community-based clinical trials network. Having such a network in place before there is urgent need will allow for increased community participation in clinical research during a public health emergency. Community-based clinical trial sites could be supported by specialized CROs, for example, and procedural and monitoring costs could be reduced by engaging a central IRB and collecting data from EHRs.
Woodcock said the creation of a community-based clinical trials network is as essential to pandemic preparedness as ensuring the availability of personal protective equipment, and thus should be a government-supported activity. “We need a national clinical trial capacity stockpile, just as we need a stockpile of medicine and equipment,” she said. She emphasized the need to regularly use such a network between emergencies to ensure it has the functional capacity needed to efficiently and effectively generate evidence. This could be done by, for example, conducting studies that answer pressing societal health questions and generate actionable evidence (e.g., studies to improve the treatment of chronic and neglected diseases). The questions, she concluded, are “Will we be prepared next time? Will we be able to respond and learn very quickly the best treatments for our patients if this happens again?”
CLOSING REMARKS
At the end of the final part of the workshop, Esther Krofah and Steven Galson reflected on the discussions that took place over the course of the workshop, which unexpectedly spanned 5 months due to the COVID-19 pandemic and the need to hold the workshop virtually. Krofah believed there was a strong sense that the experience of the COVID-19 public health crisis had created momentum for change. The discussions at the workshop were informed and influenced by the collective pandemic experience of the workshop participants, and many actionable steps toward achieving a transformed clinical trials enterprise for 2030 were discussed. Krofah noted that the U.S. government is undertaking efforts to learn from the experiences of COVID-19 clinical trials, and there are lessons to be learned and leads to follow from the CTTI vision for clinical trials in 2030 and the efforts of the TransCelerate biopharmaceutical member companies. Galson said a silver lining in the pandemic response is the ability to learn from “the real-life examples of the problems with our chronic lack of inclusiveness, and our challenges with bringing people together in a way that creates data that are actually useful for the health care system.” He urged participants to take advantage of the momentum and apply these lessons now to transform the clinical trials enterprise for the coming decade.
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