7

Reflections and Key Takeaways

The workshop concluded with featured presentations and conversations in which speakers reflected on the workshop and considered forward-looking opportunities to better engage older adult populations in clinical research and clinical trials. Appleby introduced the three speakers, representing NIH, private industry, and FDA, and moderated a panel discussion to close out the workshop.

TRANSPARENCY AND ENGAGEMENT

“Sunshine is the best disinfectant,” said Bernard, quoting former Supreme Court Justice Louis Brandeis. The NIH strategy has been to leverage policy to allow more “sunshine” onto the issue of underrepresentation of older adults in clinical trials, she said. Bernard told participants about several of these policies and initiatives at NIH.

The Inclusion Across the Lifespan (IAL) policy (Bernard et al., 2018) will require sponsors to provide anonymized individual-level data on age at enrollment, sex/gender, and race/ethnicity, which will allow NIH to see what is happening with enrollment at a granular level. Because these data are potentially identifiable information, Bernard said, it will only be available to the public in the aggregate. In addition to the IAL policy, NIH also has a mandate to share demographic data from the Research, Condition, and Disease Categorization system.¹ These data can be aggregated into a

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¹ For more information, see https://report.nih.gov/rcdc/faqs.aspx (accessed November 11, 2020).

report that displays the typical representation of participants in studies associated with a specific research, condition, or disease category. There is also a requirement for NIH grant recipients conducting Phase 3 trials to conduct and report analyses by sex/gender, race, and/or ethnicity on the website ClinicalTrials.gov. This requirement could potentially impact institutions because NIH could withhold funds for future clinical studies if the required reports are not made, Bernard said. One last “sunshine” policy is a requirement that a final Research Performance Progress Report² be submitted “for any grant that is terminated and any award that will not be extended.” This will provide the public with an opportunity to see the outcomes of NIH clinical studies “in a way that was not feasible previously.”

In addition to these policies, said Bernard, the NIH inclusion policy officer is cochairing a diversity collaborative with the Clinical Trials Transformation Initiative.³ This collaborative is working to develop resources to demonstrate the value of increasing diversity in clinical trials and adopting practices that include diverse populations in the development process for drugs and devices. Specifically, said Bernard, the collaborative’s objectives are to recommend organizational level-of-practice changes, disseminate evidence needed for decision makers to commit sufficient resources for diversity, and identify factors that yield clinical, scientific, or financial return on investment.

Finally, Bernard mentioned that NIH held the second IAL workshop in September 2020.⁴ This workshop further amplified the issues raised at the first NIH IAL workshop, as well as at this workshop.

PRACTICAL APPLICATION OF SCIENCE AND POLICY

A number of innovative and creative ideas were presented at the workshop, said Robert Califf, head of clinical policy and strategy at Verily and Google Health. However, to channel these ideas into real change, shifts are needed in the way that money flows. Changing policies can alter the flow of money, said Califf, by altering the incentives for various stakeholders. Califf noted that a workshop on the topic of drug development and older adults was held by the National Research Council 30 years ago (NRC, 1990), and “everything that was said at that meeting pertains today.” While science has advanced considerably, the practical application has fallen short.

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² For more information, see https://grants.nih.gov/grants/rppr/index.htm (accessed November 11, 2020).

³ For more information, see https://www.ctti-clinicaltrials.org/projects/diversity (accessed November 11, 2020).

⁴ For more information, see https://orwh.od.nih.gov/about/newsroom/events/nih-inclusion-across-lifespan-ii-workshop (accessed November 11, 2020).

Califf presented seven observations and suggestions, based on the discussions at the workshop as well as on his experiences in his current and prior work. First, the basic issues about pharmacology and aging are unresolved, and industry needs an incentive or requirement (i.e., a carrot or a stick) to remedy this problem. Califf noted that it is law that drug developers must study pharmacology in children if they intend to treat children,⁵ yet older adults continue to be underrepresented in clinical trials despite being the consumers of a sizable proportion of drugs (Levit et al., 2018). Second, NIH has a relevant institute and a precedent of successful implementation of policies requiring representation of underrepresented populations in clinical research. NIH’s IAL policy will work, said Califf, if there is follow-through. “When you hold people accountable in their grants to do what the policies say,” it is amazing what can happen, he said. Third, Califf said the complexity of comorbidity and polypharmacy is “daunting” and there is a need for a dedicated stream of research in this area. Research on individual issues will “not solve the problem”; rather, there is a need for a holistic approach that integrates research along the spectrum from basic pharmacology to aging organs to the phenomenology of frequent transfers between a hospital and an assisted living facility.

Califf’s fourth suggestion is that many of these issues can only be addressed by integrating research and clinical care. While there are many promising approaches for doing so, he said, his experience shows that many health systems are “actually evolving in the opposite direction.” One reason, he said, is that there is little to no reimbursed time for clinicians to participate in research. When a clinician has 10 minutes for a patient and it takes half an hour to explain a consent form, he said, it is not workable. Califf noted that there is an option in Medicare billing that provides reimbursement for involving patients in research as part of the clinic visit. This is one of many strategies that could be used to overcome this barrier, he said.

Fifth, Califf said that there is a tension between the general ethical position that people, particularly vulnerable populations, should be protected from research versus the substantial lack of evidence for informing clinical practice when it comes to treatment for older adults. It is critically important to conduct research to inform evidence-based practice, and research should be considered “a fundamental normative ethical stance of clinical practice.” There is a need to conduct empirical research to determine how to reach a balance between participation and protection, he said, particularly in regard to vulnerable populations.

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⁵ For more information, see https://www.fda.gov/science-research/pediatrics/best-pharmaceuticals-children-act-and-pediatric-research-equity-act (accessed November 11, 2020).

Sixth, there is a need for funding to capture, curate, integrate, and analyze the surplus of data from digital data streams, he said. Currently, the multiple streams of digital data are not well integrated to enable facile integration of biological, clinical, behavioral, social, and environmental factors. Califf likened the situation to the old story of the blind man and an elephant. Until recently, the blind man could only examine one part of the elephant at a time. Now, with access to large volumes of data, “we can look at the environment at which the entire herd is operating,” but limitations remain in the ability of researchers to analyze the data in a way that leads to meaningful conclusions.

Finally, said Califf, there is a need to focus on the millions of people living in the special environments of assisted living, nursing homes, and hospice care. These environments are “fundamentally different” from others, and there is a need for specific approaches to open up the research and quality efforts in those environments.

ENABLING INNOVATION

Amy Abernethy, principal deputy commissioner of food and drugs at FDA, made some observations about the workshop discussions based on her time at the agency as well as her work as a clinical trialist. First, she said, there was a recurring theme around leveraging policies and financial investments to drive forward innovation. Abernethy mentioned two policies that had been raised during workshop discussions: (1) the Orphan Drug Act,⁶ which gives sponsors increased flexibility for submission of orphan drug designation requests—providing financial incentives for developing drugs for rare diseases; and (2) pediatric drug development policies, which require companies to assess safety and effectiveness of new drugs/biologics in pediatric patients and provide financial incentives for companies to voluntarily conduct pediatric studies. These types of policy approaches may serve as enabling forces for drug development areas that need attention. There are other types of enabling policy options as well, including the use of real-world evidence and partnering with CMS to pair coverage with evidence development.

Second, workshop discussions emphasized the importance of implementation and familiarity with particular approaches. Abernethy explained that even if high-level policies are in place to encourage study protocols that facilitate enrollment of older adults, familiarity with these concepts should be acceptable to the regulatory reviewers who are ultimately responsible for reviewing applications and approving drugs. The issues surrounding drug development for older adults are complex, and may seem overwhelming to

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⁶ For more information and relevant excerpts of Public Law 97-414, see https://www.fda.gov/industry/designating-orphan-product-drugs-and-biological-products/orphan-drugact-relevant-excerpts (accessed November 11, 2020).

think about tackling. It is important, she said, to acknowledge the complexity to start working through solutions. It will also be critical to learn from the lessons gleaned from research and clinical care during the COVID-19 pandemic, and consider how these lessons may be applied in the future.

Third, said Abernethy, the breadth of presentations at the workshop demonstrated the importance of considering the totality of evidence and using multiple sources and methods to build up the evidence base. For example, data from sources such as EHRs, remote sensors, and wearables can be partnered with data acquired from adaptive design trials or platform trials. It may be necessary, she said, to determine safety and efficacy in small populations, and then expand understanding using real-world data in Phase 3 or postapproval. Stakeholders will need to measure and learn from PROs as well as clinician outcomes to better understand the full picture. Combining sources and methodologies will be critical to furthering understanding of the older patient.

“The way that we currently design our clinical trials is tough,” said Abernethy. Stakeholders should consider ways to modify clinical trials so they are more patient centered; implementation science and patient involvement should be incorporated during the first steps of planning a trial. She added that modification of clinical trials should be accompanied by an examination of how the modification may impact the integrity of the data. Relatedly, technological innovations for research or clinical care should be designed for the patients to meet their needs. At the same time, researchers and providers should communicate and partner with technology developers to ensure that new innovations address the medical need.

Finally, said Abernethy, it is critical that humanity and personhood be incorporated throughout the drug development life cycle. Particularly when working with older adults who may have experienced numerous complexities in life, stakeholders should “have compassion for all and recognize that this is hard and that we are going to have to all work in order to make it better.”

DISCUSSION

Policy Considerations

Appleby noted that NIH and FDA already had policies in place to ensure appropriate inclusion of various populations in clinical research.^7,8

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⁷ For more information on NIH policies, see https://www.niams.nih.gov/grantsfunding/conducting-clinical-research/trial-policies-guidelines-templates/nih-federalguidelines (accessed November 11, 2020).

⁸ For more information on FDApolicies, see https://www.fda.gov/regulatory-information/search-fda-guidance-documents/enhancing-diversity-clinical-trial-populationseligibility-criteria-enrollment-practices-and-trial (accessed November 11, 2020).

He asked Bernard to comment on why new policies—such as the IAL policy—might be more effective than these policies. Bernard replied that the IAL policy is “an opportunity that really has not previously existed” because it is the first to specifically mandate the inclusion of older adults. Furthermore, additional tools are in place now, such as reporting requirements, which may increase the “peer pressure” on researchers to enroll appropriate populations in trials. This peer pressure, combined with the “real pressure that can be brought to bear by agencies such as NIH and FDA,” will act as levers to move things in the right direction. Abernethy added that one important contribution of any policy is seeing “what it looks like for these policies to be in action.” Important steps are for clinical trialists to see what it looks like when eligibility criteria are widened, for companies to see that FDA is comfortable with these changes, and for statistical reviewers to consider how changes may affect the analysis plan. As has been learned from COVID-19, she said, “there is a lot to be learned just by doing it and then adjusting along the way.”

Califf noted that NIH has considerable power to enforce policies because it decides whether researchers get their next grant. He asked Bernard if NIH was planning to require that clinical trials enroll groups of people (e.g., those 65 and older) in the same proportions as they are in the population. Bernard responded that “the NIH position is that the distribution of subjects in a study should be in keeping with the scientific question that is being asked.” For example, a study about Alzheimer’s would be expected to enroll a large proportion of older adults, whereas a study on infant pneumonia would not. Ensuring that there is scientific justification for the age distribution in a trial, said Bernard, falls to the Peer Review Panel⁹ as well as monitoring by the specific institute. There is a recognition at NIH of the need for more systems to monitor and track whether the NIH-supported studies are meeting their goals in a timely fashion, she said.

Impact of COVID-19 on Research and Clinical Care

Much discussion took place during the workshop about the recent changes to research and care due to COVID-19, said Appleby. Given these changes, such as the rapid uptake of telehealth, he asked Abernethy to comment on whether some of these changes might be permanent. Abernethy responded that FDA is committed to learning from the pandemic and understanding how it may lead to changes in the future. The changes that have been made for clinical trials during the COVID-19 pandemic fall

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⁹ For more information, see https://grants.nih.gov/grants/peer-review.htm (accessed November 11, 2020).

into three categories, said Abernethy. The first were changes that were already under way, which FDA had supported in the past. For example, remote monitoring had already been highlighted in prior guidances. The second category is changes that are directly related to the public health emergency, such as making an investigational product available from a nearby physician rather than requiring trial participants to travel to a clinical trial site. These types of allowances will be removed when the public health emergency is over, she said, but she recognized that there is an opportunity to learn from these modifications going forward. The final category is the current conduct of clinical trials. In the future, said Abernethy, all three of these categories will come together: The changes that were already occurring will be amplified, stakeholders will learn from the practices that have been liberalized, and necessary additional features will be recognized.

Pediatric Exclusivity Provision

In 1997, Congress enacted a provision that provides companies with 6 months of marketing exclusivity in return for conducting pediatric studies.¹⁰ Appleby asked Califf if a similar model might be feasible to incentivize drug studies among the older adult population. Appleby said that emerging research shows that drug interventions may be able to slow the onset of multiple chronic diseases, but the issue is whether there are adequate incentives to pursue this line of drug development. Califf responded that there is no question that the pediatric exclusivity provision has driven a huge change in the inclusion of children in studies. However, he recognized that the provision has also been somewhat controversial given that some might think that the pharmaceutical industry should already be including pediatric populations in trials. He noted that the big push was for drugs that were not targeted for children, but that had a high sales value for which 6 months exclusivity would make an enormous difference. “Getting the balance right on these incentives is absolutely critical,” he said. In addition to pediatric exclusivity, there are other incentives such as the orphan disease program and the accelerated approval program. Expanding these types of incentives, he said, may result in a situation where there could be a negative incentive to tackle the common chronic diseases, which cause the majority of death and disability in the United States. While no one “in their right mind” would argue against the progress that has been made in rare diseases and cancer, there is a need to address these issues and strike the right balance going

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¹⁰ For more information, see https://www.fda.gov/science-research/pediatrics/pediatric-exclusivity-provision (accessed November 11, 2020).

forward. Abernethy agreed with Califf’s assessment, and noted that the concept of personalized medicine could result in a scenario in which “everything starts to look like a rare disease” because of increasingly narrow indications (e.g., older adults with sarcopenia and heart disease). When there are incentives for developing products for rare diseases, she said, stakeholders should consider how this approach might impact the development of products for common conditions that affect a large number of people. Califf emphasized the point that incentives are effective mechanisms for industry, so they should be aligned with medical need. The United States, said Califf, is in last place in health outcomes among financially high-income countries (Squires and Anderson, 2015), and the COVID-19 crisis has made it worse. “When the dust settles, we have some work to do in this country,” he said, to improve on past practices and to develop new approaches.

Engaging Underrepresented Populations

Although the focus of this workshop is on the inclusion of older adults in clinical trials, said Appleby, the disproportionate impact of COVID-19 on communities of color has highlighted the issue of under-representation of diverse populations in clinical trials. Appleby asked panelists to comment on what is being done to address this issue, both in general and in trials specific to COVID-19. Abernethy responded that FDA views this as important, and it is not sufficient to simply give it “lip service.” As an example of FDA’s efforts, Abernethy said listening sessions are held for medical reviewers and scientists at FDA where they can hear and understand the practical impact of diseases on real families from many different backgrounds. From a clinical trials perspective, it is critical to understand how drugs may perform in different racial or ethnic groups, and to conduct trials with specific populations to address these differences. Abernethy stressed that to increase diverse enrollment, “you cannot just say we are going to increase numbers.” Enrolling people from different ethnic and racial backgrounds may take a commitment of additional education, engagement, time, and energy.

Califf spoke about innovative ways to reach underrepresented populations, such as specifically targeted advertising, particularly on social media. He noted that using data gleaned from the Internet to offer people the opportunity to be involved in research can be a “delicate issue” because the same approach is used for traditional advertising to “extract money from people.” He added that “finding that right balance is a challenge, but [Google] is working hard on that.” Without an active effort to reach and enroll underrepresented groups, “it is very predictable” that studies will be short on minorities and older people. Phase 3 trials for

COVID-19 vaccines are just starting, said Califf, and he is optimistic that minorities and older adults will be well represented. Califf said there is a strong argument for overrepresentation of these groups because they are among those who will need the vaccine first.

ClinicalTrials.gov

A workshop participant noted that there is a perception that the website ClinicalTrials.gov may not be updated frequently enough, and asked panelists whether there are plans to improve the website. Bernard responded that ClinicalTrials.gov is managed through the National Library of Medicine, which is in the process of redesigning the website to make it as accessible and user-friendly as possible. In addition to this effort, Bernard reiterated that there is a requirement for studies to provide final data within 1 year of finishing a study. Califf added that there is a court ruling that requires sponsors to go back and fill in non-reporting from previous years, but how this will play out is unknown. These changes, said Bernard, will make it an even more useful resource. Due to the increasingly rich data available at ClinicalTrials.gov, said Califf, there is an opportunity for organizations to play an intermediary role by using the data to “translate it into something that is actionable.” Abernethy noted that FDA has used data from ClinicalTrials.gov to better understand the portfolio of clinical trials in cancer. What FDA found, she said, was that there seemed to be a mismatch between the trials and the medical needs of people: “We were not shooting our arrows in the right place.” This type of use of ClinicalTrials.gov is one way to better understand deficits when it comes to clinical trials and can help stakeholders think through how to do it better, she said.

REFLECTIONS

Appleby asked the three panelists to give 1-minute summaries of their thinking on the issues discussed at the workshop, and the likelihood of seeing meaningful progress on inclusion of older adults in clinical trials in the next 5 years.

Bernard said that she believes the field is making substantial progress. She noted that when she was a practicing geriatrician, she had to use data from younger populations and try to apply this information to 80-year-old patients. The changes that are ongoing make it likely that when she is 80, there will be appropriate data such that her physician could better guide her care, she said. Bernard said that she is optimistic and hopeful that there will be visible changes in approach within the next 5 years. This shift will require that researchers and sponsors adhere to the rules about

not excluding older adults, and that recruitment and retention practices be reconfigured to enhance enrollment of this patient population.

Califf noted that the United States is in the midst of a decline in life expectancy due largely to increased morbidity and mortality from chronic diseases in older people and people who have been disadvantaged in society.¹¹ However, he said, if policy changes are made to shift incentives, he has “complete confidence in the ingenuity of American researchers and health care entities and others” to fix this problem.

Abernethy concurred with the need for policy change, but stressed the importance of “demonstrating what is possible in creating implementation familiarity.” Once the right policies and structures are in place, she said, “American ingenuity” will take researchers where they need to go.

At the close of the workshop, Appleby offered his thoughts on the major themes that were heard over the 2-day workshop, and identified some take-home messages that stood out:

• Heterogeneity: The high degree of interindividual heterogeneity in the older population is still not fully appreciated; this should be considered when clinical trials are designed and implemented for 65+, 75+, and 80+ populations.
• Justification for exclusion: There is continued reluctance to include older adults in early-stage trials; there should be strong justification for any exclusion criteria as they relate to older adults.
• Impact of COVID-19: The COVID-19 pandemic has changed the way that research and clinical care are conducted, and there is a great deal of innovation occurring. Researchers have learned that many of these process changes may result in more efficient approaches in a post-COVID-19 environment. There is considerable interest in making many of these changes more permanent.
• Innovative designs: There are clinical trial designs available that offer promise for increasing enrollment of older adult populations, including adaptive platform trial designs, home-based trials, mechanistic modeling, clinical trial simulation, real-world data, and pragmatic clinical trials. Clinical trials can be carried out in many environments, including, for example, at home, in barber shops, and in pharmacies.

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¹¹ For more information, see https://www.cdc.gov/aging/disparities/index.htm (accessed November 11, 2020) or https://www.cdc.gov/nchs/nvss/life-expectancy.htm (accessed November 11, 2020).

• Patient-centered research: Patients and caregivers should be full partners in clinical trials and the language used is critical in this regard. For example, as Collyar said, the saying that a patient has “failed” a treatment is inaccurate and could come across as blaming the patient. “Patients do not fail treatment, treatments fail patients.”
• Access to technology: “Access to home digital technology in the COVID era and beyond is access to health care,” said Ramsdale. There is a critical need in the United States to address this issue and to make sure that broadband is fully available in all geographic areas and across socioeconomic divides.
• Incremental change or sea change: Canin asked whether COVID-19 would lead to incremental change or a sea change in the conduct of clinical trials and health care in general. More broadly, asked Appleby, will there be a sea change in the systems that perpetuate ongoing health disparities? Appleby concluded with his hope that this workshop will “begin to catalyze a sea change in how older adults are included in clinical trials going forward.”

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