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6 Reflections on the Workshop and Potential Future Directions In the final session of the workshop, moderators from the previous four panels shared their takeaways from the dayâs proceedings, which was followed by an open discussion on potential next steps. SESSION 1: OPPORTUNITIES TO IMPROVE CLINICAL TRIALS Clay Johnston reiterated the point that traditional clinical trials are becoming more expensive, inefficient, and inaccessible over time. Given this dysfunction, he highlighted the need for the next generation of clinical trials, which, of course, should incorporate new technologies. Johnston then emphasized comments by workshop participants, such as the importance of using human-centered design and seeking input from patients early in the trial design process. He noted that several speakers stated that the main barriers to progress were a lack of will and creativity. If that is the case, he pointed out that education, reassurance, and demonstrating value would be key to changing the way clinical trials are run. Linda Brady echoed some of Johnstonâs comments, adding that while there is reluctance across the different sectors for various reasons (e.g., concerns about the regulatory path forward, lack of experience engaging patients, or fear of the technology), the time to move forward is now. Brady said there seems to be opportunities for the National Institutes of Health (NIH) to do more in this space. SESSION 2: EXPLORING CLINICAL TRIALS Recapping the highlights of Session 2, Kelly Simcox said that remote digital tools are clearly having success in clinical care. What still needs to be defined, she said, is how to use these tools in a clinical trial beyond observational studies. Interventional clinical trials have made good use of virtual or direct-to-participant methodologies when digital tools are incorporated into the trial design from the beginning rather than when a traditional clinical trial, with all of its complexity, is later modified to incorporate digital tools. Another point she made regarding interventional trials was the importance of considering what patient access to data looks like in the virtual environment. Although returning data to patients in a virtual environment should be easier, the challenge is how to do this effectively and quickly, she said. Another challenge in this space regards validating a participantâs identity in a remote setting. PREPUBLICATION COPY: UNCORRECTED PROOFS 53
54 VIRTUAL CLINICAL TRIALS: CHALLENGES AND OPPORTUNITIES Simcox noted that there is still work to do regarding the use of electronic health record data given that some of these data may not be reliable or may be missing. She also pointed to the need to have more visibility regarding what clinical trials are occurring in the direct-to- participant space and the need to share the learnings gained from those trials so that direct-to- participant trials can move past doing pilots and become part of the mainstream of clinical trial methodology. SESSION 3: ACCESS AND EQUITY Kathy Hudson and Rebecca Pentz recapped some of the key points they heard. They emphasized the importance of relaxing exclusion criteria when they are not needed, so that equitable participation in clinical trials can be increased. Another point they raised was the importance of continuous dialogue with patients throughout the entire trial process from design to completion to adequately capture their input. Hudson and Pentz also emphasized the importance of community engagement, noting that coordinating with community- and faith- based organizations, such as the African Methodist Episcopal Church in the African American community, can build trust in the trial process. Furthermore, returning data to community members in real time can empower participants and make them feel like partners in the clinical trials team. It will be important, they emphasized, to include partnering community organizations in the trial budget. If the goal of a study is to identify ethnically or disease severity-linked biomarkers, Hudson and Pentz noted that it will be important for investigators to think creatively about ways to engage diverse populations. SESSION 4: POLICY CONSIDERATIONS John Wilbanks said his key takeaway from the fourth session related to the disconnect between the technology needed for virtual trials and the policy environment. He also highlighted the importance of paying attention to the impact that policies may have on clinical trials, particularly given that most trials will be hybrids of clinic-based and decentralized trials in a way that does not necessarily align with the current policy infrastructure. He noted that industryâs aversion to the risk of running afoul of regulations is something that policy can ameliorate through guidance. One subject that did not come up, but that concerns Wilbanks, is the need to think seriously about the technical security associated with consumer-grade digital health technologies, which he said are âbleeding data out into the universe.â Along those same lines, he noted the importance of consent as an ongoing relationship, not a one-time transactional gate, when digital health technologies are passively collecting data. Wilbanks suggested that the field look for places where federal and state regulations could be harmonized. He also suggested there could be ways to create âsafe harborsâ that would enable researchers to experiment and validate new approaches. David McCallie added that he came to the workshop thinking that observational and interventional trials were two distinct types of trials, but he now sees more of a gray scale of gradation between those two. The regulatory environment changes along that continuum and can sometimes lead to confusing, overlapping, and conflicting policies. To address this problem, he emphasized the value of creating a taxonomy of the spectrum of methodological choices. Doing so, he suggested, could result in clever approaches for attacking the problems that research and clinical trials are trying to address without going through the formal clinical trial channel. PREPUBLICATION COPY: UNCORRECTED PROOFS
REFLECTIONS ON THE WORKSHOP 55 NEXT STEPS Johnston discussed the value of establishing a regularly updated knowledge repository for sharing information and lessons learned based on ongoing and completed virtual trials (e.g., HIPAA considerations and state-based policies). Leanne Madre noted that as part of its mobile clinical trials programs, the Clinical Trials Transformation Initiative is creating an online resource of feasibility studies using mobile technologies. Initially, this resource will include published examples, but it might be possible to broaden the scope of this resource, said Madre. Brady remarked that the NIH Health Care Systems Research Collaboratory may also be able to host a resource portal. An unidentified workshop participant said some of the elements that might be included in such a knowledge repository may already be in place (e.g., TransCelerate resources), but it is also important to partner with the U.S Food and Drug Administration and NIH to ensure that perspectives and contributions include stakeholders in addition to the pharmaceutical industry. Necessity of an Ontology Johnston emphasized the power of using meaningful and defining language to describe the types of clinical trials discussed in this workshop. He noted that the planning committee for this workshop struggled with the term âvirtual clinical trial,â testing out and dismissing other terms (e.g., decentralized, digital health-enabled). Cummings commented that there is not going to be one term that covers all of the important characteristics of the trials discussed at the workshop, but âflexible clinical trialsâ and âdirect-to-participant trialsâ may serve as useful umbrella terms. He suggested that a âvirtual clinical trialâ may describe a study in which data are collected passively or actively using digital technologies. A few workshop participants, including Rodrigo Garcia from EMD Serono and Ray Dorsey, favored the term âmodern clinical trials,â which could imply a need for new guidances, rules, legislation, and governance mechanisms. Garcia said it is important to remember that technology should be used to enhance research by transforming the experience of trial participants. A few workshop participants, including Garcia and Ray Sharma, spoke in favor of decentralization to bring the patient into focus and improve access to participation. Sally Okun suggested using the term â21st century trialsâ based on the 21st Century Cures Act, which could harness the power of a term that is already familiar across federal agencies. Considering the speed at which technology evolves, an unidentified workshop participant suggested leaving some flexibility in the terminology to accommodate future innovation. Addressing Regulatory Policy Johnston suggested that the workshop participants have the potential to work with various organizations to advocate for policies that would better support virtual trials. Hudson added that a number of regulatory policy issues stand in the way of modern and traditional clinical trials. She mentioned these issues could benefit from thoughtful policy analysis and policy recommendations as well as advocacy for implementation. Hudson, Johnston, and Cynthia Geoghegan emphasized that it will be critical to have active patient leadership engaged in policy discussions. Wilbanks emphasized the need for better harmonization when it comes to the application of HIPAA at the state level. Deven McGraw remarked that while the U.S. Congress has the ability to pass legislation that preempts state laws, it must articulate a reason that doing so is PREPUBLICATION COPY: UNCORRECTED PROOFS
56 VIRTUAL CLINICAL TRIALS: CHALLENGES AND OPPORTUNITIES constitutionally permitted. Absent that, she said, the federal government could make a powerful and persuasive statement to state boards that regulate drug distribution and telemedicine, for example, by laying out how it interprets this space. This latter approach, which does not overturn state laws, is likely to be the path of least resistance, she added. Craft cited one example of federal regulations that bypasses conflicts with âstateâs rights that allows any physician who works for the U.S. Department of Veterans Affairs (VA) to treat patients at any VA facility in the country, regardless of state licensure provisions. Craft then suggested one small step that Congress could take, which would be to carve out an exemption to state laws for telemedicine- based clinical research or telemedicine-based clinical research for rare diseases, each of which represents a tiny slice of medical practice. McCallie commented that an economic analysis comparing traditional trials versus virtual trials could help identify challenge areas and potential advocates. For example, virtual trials may create opportunities for local physicians, who might serve as advocates for changing state regulations. Governance and Patient Engagement Johnston noted that virtual trials may require greater inclusion of patients in the design and governance than traditional clinical trials. However, Craig Lipset and Steven Cummings pointed out that more involvement of patients in the governance process is needed for all clinical trials. Furthermore, it would be beneficial if patients were included on drug safety monitoring boards, noted Cummingsâa trend he hopes NIH will recommend across its individual institutes. Hudson remarked that although talking about engaging patients throughout the clinical trials process is easy, doing so in a meaningful way is difficult. What is needed to make patient engagement work, she said, are resources that provide guidance for meaningful engagement and bidirectional training for everyone involved in a project. Geoghegan and Pentz agreed with Hudson and added that there is a need for a workforce and cadre of patient advocates trained in patient-focused drug development and 21st century clinical trials. PREPUBLICATION COPY: UNCORRECTED PROOFS