The workshop concluded with reflections and consideration of next steps for spurring innovation in drug R&D for prevalent chronic diseases. Anantha Shekhar from the University of Pittsburgh and Carlos Garner from Eli Lilly and Company moderated a panel discussion in which Susan Schaeffer and Bettina Drake of the Washington University School of Medicine, Howard Rosen from BonVelo Ventures, and Grace Colón summarized workshop key themes and highlighted some of the cross-cutting strategies discussed over the course of the workshop.
Schaeffer recognized that “knowledge gaps that are discouraging investment in R&D for prevalent chronic diseases are far too big for any one company or institution to fill.” Instead, developing treatments for prevalent chronic diseases will require broad systemic collaborations to reduce cost and risk. Several speakers had proposed establishing an Operation Warp Speed for prevalent chronic diseases to jump start innovation and accelerate progress.
Patients must be an integral part of such collaborations, Schaeffer stated. Any time that a development process does not include representation from the patients who are the expected beneficiaries of that process, “we miss out” because the process does not include relevant information about the patient experience and what patients need from new medicines. The lack of information and understanding, in turn, increases development risks and limits the potential benefits of the treatment for patients. Colón added that motivating patients and their caregivers is crucial, but challenging, because there has been so much frustration and failure relative to the potential treatments for many prevalent chronic diseases. She said that patients are savvy about what to expect from a new drug or therapy, and will be drawn to the promise of real innovation.
Drake emphasized the importance of engaging patients and incorporating their input throughout the research life cycle, including early-stage study design. By working with patients and community members in clinical trials, she added, researchers have an opportunity to build trust. Particularly at
large research centers, she said, there is no lack of patients who are passionate about their condition and want to help the next generation, their family members, or society in general, so there is no excuse for not including patient voices throughout the R&D process. For example, Schaeffer added, if basic research studies are carried out using material from biorepositories that are biased toward individuals of European descent, clinical studies farther downstream in the development process may yield drug products that do not work as well in other populations or have differential toxicity effects. For this reason, it is crucial to include diverse populations throughout the research process—from basic exploratory research to clinical trials.
Schaeffer emphasized that physician engagement, particularly among community physicians, is also important. This is especially relevant when it comes to certain chronic diseases that may lead to stigma and blame placed on patients with such conditions, she said. For example, obese patients with severe osteoarthritis may be told that the solution for their pain is to lose weight even if they have already made dietary changes and their osteoarthritis makes it difficult for them to exercise. “We need to engage physicians,” Schaeffer said, “and we need to break through this cultural idea that these conditions are either inevitable, unfixable, or due to poor lifestyle choices or poor patient decisions and characterize this as a research question that needs to be invested in and a series of conditions that actually we can improve.”
The good news, Schaeffer said, is that patient advocacy organizations and community-based organizations can help establish more patient-oriented research priorities. As an example, she referred to Russ Paulson’s presentation in the first workshop session in which he described how UsAgainstAlzheimer’s went out into the community to talk to individuals living with AD and their caregivers about what is important to them. What they learned from this work was that patient concerns did not align with typical primary outcome assessments for AD clinical trials. Similarly, Christin Veasley from the Chronic Pain Research Alliance described what is important to chronic pain patients. The chronic pain is only part of it, Schaeffer said. It can lead to problems such as brain fog, depression, fear, and sleeplessness, but these problems are not necessarily captured in a numerical, visual, analog scale for pain. She reiterated Veasley’s point that by communicating what is most important to patients, patient advocacy organizations can help establish research priorities and identify where new tools and more knowledge are needed.
Another way that patient advocacy organizations can help tackle research issues, she said, is by helping to organize and fund collaborations aimed at answering some of the big questions about prevalent chronic diseases. They can help with recruiting patients when researchers are ready to begin clinical trials and with the dissemination of research results in
ways that are understandable and meaningful to the individuals who are most affected by a particular chronic disease. Schaeffer stated, “We need to ensure that incentives are aligned for both the patient communities and the research communities to collaborate in partnership to answer these questions and break through barriers to innovation in R&D for prevalent chronic diseases.”
In closing, Schaeffer repeated a comment she had heard from Heather Gainsworth, a researcher from The University of British Columbia who has worked to develop a set of guiding principles for collaborations between individuals with spinal cord injury and researchers working to understand and treat such injuries. Gainsworth said she often hears from researchers that they would like to engage with patients, they understand that it is important, and they even believe it is the right thing to do, but it takes time. What Gainsworth tells the researchers, Schaeffer said, is that if their goal is to produce publications, then yes, it takes longer to communicate with patients. However, if their goal is to generate knowledge that can be translated into patient care that improves lives and improves outcomes, then it is actually faster to work with patients.
A major theme cutting across several of the workshop sessions, Drake said, was the importance of a patient-centered approach in designing clinical trials. The conclusion by Karen Winkfield, executive director of the Meharry-Vanderbilt Alliance, was that patients and community members should be included at every stage of the process. “By doing this,” Drake said, “you not only build trust, but you are able to incorporate feedback all along the process.” One consideration is how best to include patients and caregivers during the early stages of drug research and development. There are opportunities to include patients in early research decisions, Drake said: They can advise on a research concept, they can review proposals and provide feedback, and they can communicate with the broader communities about the value and impact of basic and clinical research.
Another theme that arose from the workshop sessions, Drake said, is the value of early intervention, which can improve patient outcomes. She emphasized the need to focus on what is most important to patients and caregivers and seek therapeutic interventions that improve their quality of life. To this end, it is crucial to seek patient input about what results matter most to them.
Some of the workshop discussions examined how changes in clinical trials triggered by the COVID-19 pandemic may affect R&D practices in the future. A number of lessons can be applied, Drake said. For example, she noted, “We are much more comfortable with e-consenting, much more
comfortable with allowing participants to enter data or collect data in their homes or to use self-sample collection kits or enter data online, which could help us reach a broader audience moving forward.”
With increasing use of digital technologies in decentralized trials, Drake noted that there are a number of new and emerging technologies for real-world data collection. For example, mobile devices can track physical activity or heart rate throughout the course of daily life. With this ability, she emphasized that there is a need for researchers to deliberately choose which specific data would be useful in a clinical trial in advance and make plans for collecting and analyzing this information.
Drake observed that “clinical trials are becoming increasingly complex, but there is room for innovation in the way they are conducted and analyzed that is acceptable not just to regulators, but also to community members and patients.”
Given that many patients experiencing chronic disease suffer from more than one disease at a time, a holistic approach that accounts for individual variability can help capture important effects of candidate treatments, said Colón. Drake added that comorbidities may vary across different populations, underscoring the importance of capturing variability in clinical trials. Colón acknowledged that including diverse populations in trials introduces new challenges. “We need to be more creative about how to design these trials with new statistical approaches so that we can include all of these populations with enough statistical power,” she said, “but also be able to do subanalyses and understand how a particular treatment or particular overall pathway is impacting these various populations.”
Schaeffer said there is an openness among regulators to approaches that involve comorbidities. One example is FDA’s guidance on including patients with brain metastases in cancer clinical trials.1 The guidance proposes an option to include patients without brain metastases for the clinical trial’s primary endpoint, but simultaneously include patients with brain metastases for secondary, subpopulation-specific analyses.
Given the many uncertainties associated with the progression of chronic diseases, the use of artificial intelligence could play a useful role in unravel-ling the mysteries of pathogenesis and analyze large volumes and types of data, said Rosen. As John Ngai explained in his remarks, NIH’s BRAIN Initiative is generating large amounts of data, as are a variety of other programs, which can be analyzed using AI approaches to inform drug discov-
ery and development programs. Interestingly, Rosen observed, data from diverse sources can strengthen algorithmic predictions. Schaeffer added that real-world evidence could help reduce the risks typically associated with drug development for prevalent chronic diseases.
Along with the potential, there are also a number of challenges, Rosen noted. Analyzing large amounts of data raises a variety of process questions, such as determining the best ways to format and share the data. What sort of formats will be accessible to the greatest number of data users? How can people be made aware of the data and given easy access to it? Large datasets containing data taken from individuals also raise a number of privacy-related challenges. These are magnified when the data are collected from small populations, such as members of indigenous populations, as noted by Erica Woodahl from the University of Montana. Schaeffer emphasized that data-heavy approaches require thoughtful consideration of patient data protection, data ownership, and governance to ensure that information is handled in an ethically responsible and equitable manner.
Overall, Rosen concluded, the workshop left him optimistic about the potential for formulating new techniques to speed the drug development process and having an impact on prevalent chronic diseases.
Colón summarized examples of past success that could offer lessons learned for innovation in drug R&D for prevalent chronic diseases going forward. Chronic diseases are complex and multifactorial, so a single drug or device is never enough, she said.
Robert Coughlin of JLL spoke passionately about a success story from CF, and Colón emphasized the power of passionate patient advocacy groups to push research forward. However, she cautioned that people do not always have the time and resources to advocate or lobby. She noted that this can be an even greater challenge for underserved populations.
Colón highlighted the importance of pushing for endpoints that reflect patient preferences and quality of life. She highlighted the IMI project on COPD,2 which led to the development of patient-reported outcome tools now in use. Those tools are particularly important, Colón remarked, because COPD is complex, and patients with COPD often have comorbidities.
The integration of patient-facing digital health tools in trials for chronic disease management, as raised by Raolat Abdulai, holds promise. Such
2 For more information on the IMI PROactive project, see https://www.imi.europa.eu/projects-results/project-factsheets/pro-active (accessed July 3, 2021).
integration requires taking a holistic look at what patients want and need, from managing their own care to carrying on in their daily lives. Engaging caregivers and allowing patients to achieve self-management should be a goal for chronic disease management, she said.
For complex diseases that affect multiple organ systems, Colón emphasized the promise of a cross-functional approach. Robert Heine, an Eli Lilly Scholar, gave an example of metabolic syndrome and its associated disorders. The syndrome is particularly worrisome because it is growing not only in the United States but globally as well, and it leads to many other comorbidities. Colón emphasized the promise in focusing on total disease burden rather than on any one endpoint. She added that because metabolic syndrome has many different implications, it is important to look at real-world evidence and understand what is happening in patients’ lives in order to understand the types of innovations that will be most valuable.
The good news, Colón said, is that a variety of companies are looking to put innovative technologies to work in every aspect of clinical trials, from risk mitigation to novel biomarkers and composite endpoints, “and so there is a lot of optimism about the future.”
Potential Opportunities for the Future
The panelists proposed a few areas in which investment and attention could spur innovation in drug R&D for prevalent chronic diseases:
- There are opportunities to rethink the overall patient journey and to develop new treatment paradigms enabled by new technologies and approaches, including modalities and routes of delivery, the optimization of formulations and device combinations, novel biomarkers, and digital health technologies. (Colón)
- Underserved populations are disproportionately affected by prevalent chronic diseases, so increased focus on the inclusion of patient and community voices across the entire R&D life cycle is needed. (Colón, Drake)
- Success in dealing with prevalent chronic diseases will require new levels of collaboration and sharing among all stakeholders: patients and advocacy groups; federal, state, and local governments; regulators; venture philanthropy; academia; the biopharmaceutical industry; payers and providers; technology developers; and more. “This is a call to action for all of us to work together on this.” (Colón)
- Leveraging public resources to address complex conditions that drive illness, and supporting collaborative initiatives to diagnose and treat early-stage prevalent chronic disease, can improve quality of life and long-term outcomes. (Colón, Drake, Rosen)
- It is important that payer incentives and health economics are aligned because secondary and tertiary costs of these diseases are often not factored into cost calculations. (Colón)
- Conducting outreach efforts supported by industry, educating patients about drug R&D, and engaging patients and communities as partners can provide valuable knowledge to improve drug R&D for prevalent chronic diseases. (Schaeffer)
- Defining and validating novel endpoints for clinical trials can help reduce the overall cost of prevalent chronic disease clinical trials and improve the relevance of studies for patients, clinicians, and payers. (Colón)
- There are opportunities for increased use by sponsors and support by regulators for using adaptive trial designs and novel data sources, such as real-world data, in rigorous analyses. (Colón)
- Private investors and venture philanthropists have opportunities to invest in companies developing novel approaches aimed at unmet medical needs. (Colón)
Ensuring that patients have access to care should be a top priority because it enables the early detection of chronic diseases and comorbidities, said Colón. Health insurance policies can also play a major role, said Rosen. Many Americans spend time without health insurance, which makes it less likely that their chronic diseases will be detected and addressed early. Rosen suggested that targeted policy changes could help improve patient access to and use of health care. Drake noted that it is important to ensure that policy changes are implemented well and that individuals take advantage of them. For example, even though Operation Warp Speed was successful in developing several COVID-19 vaccines, the vaccine rollout and uptake varied across the country. Similarly, even if insurance policies are put in place, individuals still need to enroll in the insurance programs and take advantage of the policies.
Robert Califf from Duke University, Verily Life Sciences, and Google Health said that economic issues are going to be an important factor in the nation’s response to prevalent chronic diseases. The U.S. government made major commitments and upfront payments that took away some of the risks for COVID-19 vaccine development for industry, but he added that this cannot be done for every disease. Economic incentives will likely play a role in spurring innovation in drug R&D for prevalent chronic diseases, he said, but it will take considerable policy discussions for how best to proceed. Colón suggested examination of the regulatory and reimbursement changes made in response to the pandemic to learn what might work for the longer term.
In closing, Garner pointed to the transparent and open dialogue among leaders, FDA, and industry, as well as the shared sense of urgency that
characterized the nation’s response to COVID-19, as a positive example of collaboration. He suggested that prevalent chronic diseases could benefit from applying that same transparent communication and sense of urgency to address the nation’s most pressing health problems.
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