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Infrastructure to Support Accrual of Older Adults to National Cancer Institute Clinical Trials

Infrastructure to Support Accrual of Older Adults to National Cancer Institute Clinical Trials Abstract As part of ongoing efforts to meaningfully improve recruitment, enrollment, and accrual of older adults into cancer clinical trials, the National Cancer Institute (NCI) sponsored a workshop with experts across the country entitled Engaging Older Adults in the NCI Clinical Trials Network: Challenges and Opportunities. Three working groups, including Study Design, Infrastructure, and Stakeholders, were formed, who worked together to offer synergistic improvements in the system. Here, we summarize the workshop discussions of the Infrastructure Working Group, whose goal was to address infrastructural challenges, identify underlying resources, and offer solutions to facilitate accrual of older adults into cancer clinical trials. Based on preconference work and workshop discussions, four key recommendations to strengthen NCI infrastructure were proposed: 1) further centralize resources and expertise; 2) provide training for clinical research staff; (3) develop common data elements; and 4) evaluate what works and does not work. These recommendations provide a strategy to improve the infrastructure to enroll more older adults in cancer clinical trials. The foundation for evidence-based guidelines in cancer care stems from evidence gained in a variety of studies, especially high-quality clinical trials. Yet, although more than half of patients with cancer are aged 65 years and older, historically, only about a quarter of patients enrolled in cancer clinical trials are in this age group (1,2). Barriers and challenges to the recruitment, enrollment, and accrual of older adults to clinical trials are multifaceted, complex, and remarkably persistent. They broadly include issues stemming from those that are physician-, caregiver-, and patient-related as well as from the medical and research system overall (3-9). In a recent systematic literature review focused on interventions to increase accrual of older adults to cancer clinical trials, only 13 high-quality studies were identified, with high quality defined as articles that were 1) empirical; 2) peer reviewed; 3) experimental, quasi-experimental, or observational; 4) evaluating barriers to participation and/or interventions to improve the participation of older adults; and 5) focused on patients aged 65 years and older with cancer (10). Most concerning, only 1 prospective randomized trial meeting these criteria was identified, and it was a negative trial (11). The systematic review highlighted the paucity of high-quality evidence that uniformly and comprehensively define barriers to cancer clinical trial accrual of older adults and found no evidence identifying effective interventions to improve enrollment of older adults. There is clearly much work left to be done. Reference to this need is made in the National Institutes of Health Central Resources for Grants and Funding Information (https://grants.nih.gov/policy/inclusion/lifespan.htm) and was recently highlighted by an expert perspective (12). In this report, we focus on the role of infrastructure in clinical trials, describe its role in the current situation and offer ways to improve that infrastructure in future trial design. It is helpful in this context to clearly state what we mean by infrastructure. Infrastructure, in this context, means the people, processes, and policies that underlie the conduct of clinical trials research. This differs from the larger considerations of structure of the entire research enterprise, both within the National Cancer Institute (NCI) and outside of it, which governs many aspects of research but is outside the scope here. This specific report, based on the conference, is focused on infrastructure, which is a component within the larger structure. Improving accrual of older adults to clinical trials will require strategic intervention at multiple levels, including the individuals involved and the infrastructural components. Importantly, the larger and most critical barriers are at the infrastructural level. How do we know this? First, certain characteristics of older adults with cancer constitute important barriers. Studies show that more than half of patients are willing to participate in clinical trials when offered (13) and that older patients are as likely as younger patients to participate (14). In fact, 3 of 4 patients with cancer will not have the opportunity to participate in a clinical trial because there is no trial available locally or they are ineligible (13,15,16). These difficulties are common for all adult patients with cancer, but are even more amplified for vulnerable groups, including the older adults. Given this, specific interventions to improve accrual must be developed, and those interventions will need to be infused into the trial designs. Trials themselves will need careful attention to this design, including broader eligibility criteria and clearer definitions of outcome measures that are more appropriate for older adults, to allow for the inclusion of as many older patients as possible. In addition, the underlying infrastructure, described below, must facilitate the participation of older adults, such that their accrual is actively pursued, breaking down the inertia of the current structures, encouraging the consistent collection of information pertinent to their needs, and offering training to staff on these needs. We should also study ways to improve the enrollment with high-quality research designs that allow greater opportunity for older adults to enroll in trials specific to their needs. Of course, infrastructure changes are only one aspect of the solution; other concerns are addressed in the companion articles in this issue. Conference Structure and Goals, Infrastructure Subgroup Coordinated by the NCI Division of Cancer Prevention in collaboration with the Division of Cancer Treatment and Diagnosis, and supported by the Cancer MoonshotSM Network for Direct Patient Engagement Implementation Team, a virtual workshop entitled Engaging Older Adults in the NCI Clinical Trials Network: Challenges and Opportunities was held April 26-27, 2021, to jump-start initiatives that will hopefully lead to improved accrual of older adult patients to cancer clinical trials. In preparation for the workshop, working groups centering on study design, infrastructure, and stakeholders were formed and met in advance to create an agenda and facilitate synergies across groups. In this paper, we describe the recommendations made by the Infrastructure Working Group, based on that agenda and the focused discussions during the conference among the members of this group who are co-authors of this manuscript. Organizers agreed that a focused approach would most likely lead to near-future changes, and the subgroups focused on actionable changes. The charge to the Infrastructure Working Group, developed in advance of the conference, is outlined in Table 1. The group focus was to address underlying resources needed to facilitate accrual and gather pertinent data specific for older adults with cancer—in other words, to suggest ways to alter current infrastructure for clinical trials that meaningfully change the core elements of people, processes, and policies that would improve recruitment, enrollment, and accrual and would standardize assessments and results across trials. Our goal was to identify achievable opportunities in the near-term, or actionable “low-hanging fruit,” within an already strong system that would strengthen the National Clinical Trials Network (NCTN) and NCI Community Oncology Research Program (NCORP) infrastructure and specifically address the barriers and challenges to engagement of older adults, families, and providers in NCI-sponsored clinical trials. Although this scope is narrow, given the many challenges faced in changing practices and influencing existing infrastructure, it is also targeted and important. For example, it focuses on the issues for older adults, one vulnerable group among many, and only indirectly benefits other vulnerable groups impacted by biased infrastructure including race, ethnicity, and gender, to name a few. This is not to diminish the importance of those groups, only to acknowledge the agenda established for this workshop and group, and it reflects the overall goal of decreasing age bias. Table 1. Charge to the Infrastructure Working Group Task . Charge . 1. Develop a roadmap from conceptualization of research question to dissemination of results, including Identification of necessary resources Consideration of the older adult throughout the process Inclusion of a recruitment plan 2. Describe resources available to investigators explaining they can access experts with aging expertise 3. Define infrastructure needs to perform comprehensive geriatric assessment 4. Describe use of technology or telehealth to engage older adults in clinical research 5. Consider approaches to accrue racial and ethnic minority older adults and those from rural areas 6. Develop a plan for the evaluation of what has worked and not worked Task . Charge . 1. Develop a roadmap from conceptualization of research question to dissemination of results, including Identification of necessary resources Consideration of the older adult throughout the process Inclusion of a recruitment plan 2. Describe resources available to investigators explaining they can access experts with aging expertise 3. Define infrastructure needs to perform comprehensive geriatric assessment 4. Describe use of technology or telehealth to engage older adults in clinical research 5. Consider approaches to accrue racial and ethnic minority older adults and those from rural areas 6. Develop a plan for the evaluation of what has worked and not worked Open in new tab Table 1. Charge to the Infrastructure Working Group Task . Charge . 1. Develop a roadmap from conceptualization of research question to dissemination of results, including Identification of necessary resources Consideration of the older adult throughout the process Inclusion of a recruitment plan 2. Describe resources available to investigators explaining they can access experts with aging expertise 3. Define infrastructure needs to perform comprehensive geriatric assessment 4. Describe use of technology or telehealth to engage older adults in clinical research 5. Consider approaches to accrue racial and ethnic minority older adults and those from rural areas 6. Develop a plan for the evaluation of what has worked and not worked Task . Charge . 1. Develop a roadmap from conceptualization of research question to dissemination of results, including Identification of necessary resources Consideration of the older adult throughout the process Inclusion of a recruitment plan 2. Describe resources available to investigators explaining they can access experts with aging expertise 3. Define infrastructure needs to perform comprehensive geriatric assessment 4. Describe use of technology or telehealth to engage older adults in clinical research 5. Consider approaches to accrue racial and ethnic minority older adults and those from rural areas 6. Develop a plan for the evaluation of what has worked and not worked Open in new tab With this scope and focus in mind, the Infrastructure Working Group made 4 key recommendations to strengthen infrastructure, described in greater detail below: 1) increase centralization of resources and expertise; 2) greater training for clinical research staff; 3) emphasis on developing common data elements (CDEs) to be used across studies; and 4) systematic evaluation of interventions to learn which interventions work best. These recommended solutions, anticipated gains, and other questions for discussion are outlined in Table 2 and discussed below. Two of the areas for improvement identified in advance of the conference—greater use of technology and intersectionality considerations of race and ethnicity and rural areas—received less direct emphasis and are embedded in the existing recommendations. Table 2. Improving cancer clinical trial accrual in older adults, recommendations from the Infrastructure Working Group . Problem . Solution . Gain . Discussion . Centralize resources and expertise Investigators do not have centralized geriatric oncology resources or access to local expertise. Develop and centralize resources: “Checklist” for concept development “Recruitment plans” (roadmap) Example protocol language Referral for support via CARinG R33 infrastructure Providing investigators with expert-developed resources and improving quality and reducing duplicative efforts around research and enrollment of older adults What resources would be most helpful? Where should these resources be housed? Can we monitor uptake of these resources? How can we encourage and/or facilitate use? How can we ensure implementation? Train clinical research staff No formal training of GA across all sites. This results in variability in instrument completion and scoring (missing data). Develop and centralize GA training: Deliver it online Track site completion Consistent training can reduce duplication of work for sites and groups and improve data collection and quality What are key GA training needs that can be addressed through online training? Develop CDEs Similar or identical GA items are often being collected in separate study databases. Inconsistency in data descriptors. Difficult to aggregate and manage aging-related data across studies. Standardize GA data nomenclature for reporting of NCI trials: Work with NCI to add CDEs for key GA items to the NCI CDE browser for use in future NCTN-NCORP trial case report forms Work with statisticians and data managers to develop Rave case report forms for key GA tools that could be adapted by individual groups and research bases Reduce duplication of effort, increase efficiency Encourage consistent centralized data collection to facilitate aggregate analyses Is it feasible to collect GA data on trials and have clinical research associates input the data in Rave? What else could be done to make it easier to collect and analyze GA data in NCTN–NCORP trials? Evaluate what works and what does not work It is difficult to implement change across all NCTN-NCORP trials. Strategic approach: Assess the current landscape Learn from diseases that are successful at enrolling older adults (high rates); meet with successful investigators and sites Target specific interventions in disease areas that are struggling to enroll older adults Using a targeted approach and learning from what works and what does not will help us pilot new ideas, show feasibility, and enhance future broad implementation How do we define successful, low, and high enrollment of older adults to NCTN-NCORP trials? What disease areas should be targeted? . Problem . Solution . Gain . Discussion . Centralize resources and expertise Investigators do not have centralized geriatric oncology resources or access to local expertise. Develop and centralize resources: “Checklist” for concept development “Recruitment plans” (roadmap) Example protocol language Referral for support via CARinG R33 infrastructure Providing investigators with expert-developed resources and improving quality and reducing duplicative efforts around research and enrollment of older adults What resources would be most helpful? Where should these resources be housed? Can we monitor uptake of these resources? How can we encourage and/or facilitate use? How can we ensure implementation? Train clinical research staff No formal training of GA across all sites. This results in variability in instrument completion and scoring (missing data). Develop and centralize GA training: Deliver it online Track site completion Consistent training can reduce duplication of work for sites and groups and improve data collection and quality What are key GA training needs that can be addressed through online training? Develop CDEs Similar or identical GA items are often being collected in separate study databases. Inconsistency in data descriptors. Difficult to aggregate and manage aging-related data across studies. Standardize GA data nomenclature for reporting of NCI trials: Work with NCI to add CDEs for key GA items to the NCI CDE browser for use in future NCTN-NCORP trial case report forms Work with statisticians and data managers to develop Rave case report forms for key GA tools that could be adapted by individual groups and research bases Reduce duplication of effort, increase efficiency Encourage consistent centralized data collection to facilitate aggregate analyses Is it feasible to collect GA data on trials and have clinical research associates input the data in Rave? What else could be done to make it easier to collect and analyze GA data in NCTN–NCORP trials? Evaluate what works and what does not work It is difficult to implement change across all NCTN-NCORP trials. Strategic approach: Assess the current landscape Learn from diseases that are successful at enrolling older adults (high rates); meet with successful investigators and sites Target specific interventions in disease areas that are struggling to enroll older adults Using a targeted approach and learning from what works and what does not will help us pilot new ideas, show feasibility, and enhance future broad implementation How do we define successful, low, and high enrollment of older adults to NCTN-NCORP trials? What disease areas should be targeted? a CDE = common data element; GA = geriatric assessment; NCI = National Cancer Institute; NCTN-NCORP = National Clinical Trials Network–NCI Community Oncology Research Program. Open in new tab Table 2. Improving cancer clinical trial accrual in older adults, recommendations from the Infrastructure Working Group . Problem . Solution . Gain . Discussion . Centralize resources and expertise Investigators do not have centralized geriatric oncology resources or access to local expertise. Develop and centralize resources: “Checklist” for concept development “Recruitment plans” (roadmap) Example protocol language Referral for support via CARinG R33 infrastructure Providing investigators with expert-developed resources and improving quality and reducing duplicative efforts around research and enrollment of older adults What resources would be most helpful? Where should these resources be housed? Can we monitor uptake of these resources? How can we encourage and/or facilitate use? How can we ensure implementation? Train clinical research staff No formal training of GA across all sites. This results in variability in instrument completion and scoring (missing data). Develop and centralize GA training: Deliver it online Track site completion Consistent training can reduce duplication of work for sites and groups and improve data collection and quality What are key GA training needs that can be addressed through online training? Develop CDEs Similar or identical GA items are often being collected in separate study databases. Inconsistency in data descriptors. Difficult to aggregate and manage aging-related data across studies. Standardize GA data nomenclature for reporting of NCI trials: Work with NCI to add CDEs for key GA items to the NCI CDE browser for use in future NCTN-NCORP trial case report forms Work with statisticians and data managers to develop Rave case report forms for key GA tools that could be adapted by individual groups and research bases Reduce duplication of effort, increase efficiency Encourage consistent centralized data collection to facilitate aggregate analyses Is it feasible to collect GA data on trials and have clinical research associates input the data in Rave? What else could be done to make it easier to collect and analyze GA data in NCTN–NCORP trials? Evaluate what works and what does not work It is difficult to implement change across all NCTN-NCORP trials. Strategic approach: Assess the current landscape Learn from diseases that are successful at enrolling older adults (high rates); meet with successful investigators and sites Target specific interventions in disease areas that are struggling to enroll older adults Using a targeted approach and learning from what works and what does not will help us pilot new ideas, show feasibility, and enhance future broad implementation How do we define successful, low, and high enrollment of older adults to NCTN-NCORP trials? What disease areas should be targeted? . Problem . Solution . Gain . Discussion . Centralize resources and expertise Investigators do not have centralized geriatric oncology resources or access to local expertise. Develop and centralize resources: “Checklist” for concept development “Recruitment plans” (roadmap) Example protocol language Referral for support via CARinG R33 infrastructure Providing investigators with expert-developed resources and improving quality and reducing duplicative efforts around research and enrollment of older adults What resources would be most helpful? Where should these resources be housed? Can we monitor uptake of these resources? How can we encourage and/or facilitate use? How can we ensure implementation? Train clinical research staff No formal training of GA across all sites. This results in variability in instrument completion and scoring (missing data). Develop and centralize GA training: Deliver it online Track site completion Consistent training can reduce duplication of work for sites and groups and improve data collection and quality What are key GA training needs that can be addressed through online training? Develop CDEs Similar or identical GA items are often being collected in separate study databases. Inconsistency in data descriptors. Difficult to aggregate and manage aging-related data across studies. Standardize GA data nomenclature for reporting of NCI trials: Work with NCI to add CDEs for key GA items to the NCI CDE browser for use in future NCTN-NCORP trial case report forms Work with statisticians and data managers to develop Rave case report forms for key GA tools that could be adapted by individual groups and research bases Reduce duplication of effort, increase efficiency Encourage consistent centralized data collection to facilitate aggregate analyses Is it feasible to collect GA data on trials and have clinical research associates input the data in Rave? What else could be done to make it easier to collect and analyze GA data in NCTN–NCORP trials? Evaluate what works and what does not work It is difficult to implement change across all NCTN-NCORP trials. Strategic approach: Assess the current landscape Learn from diseases that are successful at enrolling older adults (high rates); meet with successful investigators and sites Target specific interventions in disease areas that are struggling to enroll older adults Using a targeted approach and learning from what works and what does not will help us pilot new ideas, show feasibility, and enhance future broad implementation How do we define successful, low, and high enrollment of older adults to NCTN-NCORP trials? What disease areas should be targeted? a CDE = common data element; GA = geriatric assessment; NCI = National Cancer Institute; NCTN-NCORP = National Clinical Trials Network–NCI Community Oncology Research Program. Open in new tab Recommendation 1: Centralization of Resources and Expertise A major challenge for clinical trial enrollment of older adults is the national paucity of expertise. Investigators typically do not have centralized geriatric oncology resources or access to local expertise. For instance, in a survey of NCORP, among 943 NCORP practices, only 2% had a fellowship-trained geriatric oncologist on staff and 37% had geriatricians available for consultation or co-management, and of those, only 13% (5% overall) had geriatricians available in the oncology clinic (17). This not only hinders care for older adults but also has implications for clinical trial accrual and available expertise for trial design. Given that this situation is unlikely to change quickly, another solution is needed. Leveraging existing resources more efficiently is one way to approach this problem. To improve resources to specifically address the unique issues that are faced by older adults with cancer and to improve accrual to clinical trials, we propose that existing national resources be further developed and targeted for this group. Furthermore, resources should be centralized, organized, and made known and accessible to health-care professionals. An additional benefit would be the impact on all patients, regardless of age, who face similar barriers of access because of shared vulnerabilities. Recommendations suggested by the Infrastructure Working Group to augment available resources are listed in Table 2. Where possible, we suggested that currently available resources be leveraged so that they can be quickly deployed. Examples are offered that can be readily adapted and applied to older adults. First, we recommend that checklists be developed and followed during clinical trial concept development and, second, we suggest that examples for standard protocol language be made available. The NCTN Adolescent and Young Adult checklist for concepts and protocols (https://ctep.cancer.gov/protocolDevelopment/docs/NCTN_AYA_Checklist_for_Concepts_and_Protocols.pdf) is an example of a successful checklist. This document provides checklists for concept stage and protocol stages of trial development and provides standardized protocol language regarding study rationale, measures, and statistical design. Another checklist, focused on older adults, has been developed for the Alliance’s Cancer in Older Adult Committee for Study Concept Review (Table 3). Such checklists provide policies and processes to ensure consistency and quality, and they could be more widely adapted across the NCI. Table 3. The Alliance’s Cancer in Older Adult Committee Check List for Study Concept Review CANCER IN OLDER ADULT COMMITTEE CHECKLIST FOR STUDY CONCEPT REVIEW Reviewed by Date: 1. Is this concept applicable to older patients with cancer (≥65 years of age)? ◻ Yes, proceed to next question. ◻ No, your review is complete and the rest of the form does not need to be completed. Additional comments for consideration: 2. Is there an upper age limit on this concept (and/or is Inclusion Across the Lifespan addressed in this concept)? ◻ No. ◻ Yes, the upper age limit is appropriate for this concept and rationale for the age cut-off is provided. ◻ Yes, the upper age limit is appropriate for this concept; however, a rationale for the age cut-off is not provided and needs to be included. ◻ Yes, the upper age limit is NOT appropriate for this concept. Please explain your concerns and provide recommendations: Note: If possible/relevant, please provide a reference(s) to support your recommendation: 3. Are inclusion criteria appropriate and as broad as possible with respect to enrolling older patients with cancer? ◻ Yes, no changes recommended. ◻ No, explain your concerns and provide recommendation: 4. Are endpoints relevant to older adults with cancer (such as the impact of treatment on function) already included in this concept? ◻ Yes, skip the next question. ◻ No, but this is not relevant to this concept. ◻ No, please consider the following endpoints relevant to older adults with cancer (comments below). Comments and recommendations: 5. Are there measures to ensure that sufficient numbers of older patients are enrolled to the study (ie, proportions of older patients enrolled reflect the proportions in the population?)a ◻ Yes, not applicable, this study is dedicated to older patients with cancer. ◻ Yes, the study design specifies the number of older patients with cancer that will need to be enrolled. ◻ Yes, other, explain. ◻ No, not applicable to this study. ◻ No, I would recommend adequate numbers of older patients be enrolled to this study. Please provide details for this recommendation: 6. Is the geriatric assessment included? ◻ Yes. ◻ No, I do not recommend that the geriatric assessment be included. ◻ No, I recommend that the geriatric assessment be included. Please provide details for this recommendation (eg, rationale for including, correlative endpoint, time points recommended): 7. Independent of the geriatric assessment, are there other core measures included for this study regarding comorbidity, or baseline blood work that should be collected? ◻ Yes, what are they? ◻ No, I recommend that the following core measures be considered: 8. Has the study team already engaged someone from the Cancer in the Older Adult Committee in designing this study? ◻ Yes (Name __________________________) ◻ No ◻ N/A I don’t think this is necessary.b 9. If this concept is approved for protocol development (and it is appropriate to add a committee member to the study team), would you be willing to serve as the Cancer in the Older Adult co-chair for this study? ◻ Yes. ◻ No, please provide a recommendation for a Cancer in the Older Adult Co-Chair: ◻ No, Older Adult Committee member not necessary. Additional comments for study team consideration: CANCER IN OLDER ADULT COMMITTEE CHECKLIST FOR STUDY CONCEPT REVIEW Reviewed by Date: 1. Is this concept applicable to older patients with cancer (≥65 years of age)? ◻ Yes, proceed to next question. ◻ No, your review is complete and the rest of the form does not need to be completed. Additional comments for consideration: 2. Is there an upper age limit on this concept (and/or is Inclusion Across the Lifespan addressed in this concept)? ◻ No. ◻ Yes, the upper age limit is appropriate for this concept and rationale for the age cut-off is provided. ◻ Yes, the upper age limit is appropriate for this concept; however, a rationale for the age cut-off is not provided and needs to be included. ◻ Yes, the upper age limit is NOT appropriate for this concept. Please explain your concerns and provide recommendations: Note: If possible/relevant, please provide a reference(s) to support your recommendation: 3. Are inclusion criteria appropriate and as broad as possible with respect to enrolling older patients with cancer? ◻ Yes, no changes recommended. ◻ No, explain your concerns and provide recommendation: 4. Are endpoints relevant to older adults with cancer (such as the impact of treatment on function) already included in this concept? ◻ Yes, skip the next question. ◻ No, but this is not relevant to this concept. ◻ No, please consider the following endpoints relevant to older adults with cancer (comments below). Comments and recommendations: 5. Are there measures to ensure that sufficient numbers of older patients are enrolled to the study (ie, proportions of older patients enrolled reflect the proportions in the population?)a ◻ Yes, not applicable, this study is dedicated to older patients with cancer. ◻ Yes, the study design specifies the number of older patients with cancer that will need to be enrolled. ◻ Yes, other, explain. ◻ No, not applicable to this study. ◻ No, I would recommend adequate numbers of older patients be enrolled to this study. Please provide details for this recommendation: 6. Is the geriatric assessment included? ◻ Yes. ◻ No, I do not recommend that the geriatric assessment be included. ◻ No, I recommend that the geriatric assessment be included. Please provide details for this recommendation (eg, rationale for including, correlative endpoint, time points recommended): 7. Independent of the geriatric assessment, are there other core measures included for this study regarding comorbidity, or baseline blood work that should be collected? ◻ Yes, what are they? ◻ No, I recommend that the following core measures be considered: 8. Has the study team already engaged someone from the Cancer in the Older Adult Committee in designing this study? ◻ Yes (Name __________________________) ◻ No ◻ N/A I don’t think this is necessary.b 9. If this concept is approved for protocol development (and it is appropriate to add a committee member to the study team), would you be willing to serve as the Cancer in the Older Adult co-chair for this study? ◻ Yes. ◻ No, please provide a recommendation for a Cancer in the Older Adult Co-Chair: ◻ No, Older Adult Committee member not necessary. Additional comments for study team consideration: a Trials should include an analysis of relevant endpoints in those aged 65 years and older that is powered to identify the differences between those endpoints. b If N/A or not necessary are checked, an explanation should be given to explain why. Open in new tab Table 3. The Alliance’s Cancer in Older Adult Committee Check List for Study Concept Review CANCER IN OLDER ADULT COMMITTEE CHECKLIST FOR STUDY CONCEPT REVIEW Reviewed by Date: 1. Is this concept applicable to older patients with cancer (≥65 years of age)? ◻ Yes, proceed to next question. ◻ No, your review is complete and the rest of the form does not need to be completed. Additional comments for consideration: 2. Is there an upper age limit on this concept (and/or is Inclusion Across the Lifespan addressed in this concept)? ◻ No. ◻ Yes, the upper age limit is appropriate for this concept and rationale for the age cut-off is provided. ◻ Yes, the upper age limit is appropriate for this concept; however, a rationale for the age cut-off is not provided and needs to be included. ◻ Yes, the upper age limit is NOT appropriate for this concept. Please explain your concerns and provide recommendations: Note: If possible/relevant, please provide a reference(s) to support your recommendation: 3. Are inclusion criteria appropriate and as broad as possible with respect to enrolling older patients with cancer? ◻ Yes, no changes recommended. ◻ No, explain your concerns and provide recommendation: 4. Are endpoints relevant to older adults with cancer (such as the impact of treatment on function) already included in this concept? ◻ Yes, skip the next question. ◻ No, but this is not relevant to this concept. ◻ No, please consider the following endpoints relevant to older adults with cancer (comments below). Comments and recommendations: 5. Are there measures to ensure that sufficient numbers of older patients are enrolled to the study (ie, proportions of older patients enrolled reflect the proportions in the population?)a ◻ Yes, not applicable, this study is dedicated to older patients with cancer. ◻ Yes, the study design specifies the number of older patients with cancer that will need to be enrolled. ◻ Yes, other, explain. ◻ No, not applicable to this study. ◻ No, I would recommend adequate numbers of older patients be enrolled to this study. Please provide details for this recommendation: 6. Is the geriatric assessment included? ◻ Yes. ◻ No, I do not recommend that the geriatric assessment be included. ◻ No, I recommend that the geriatric assessment be included. Please provide details for this recommendation (eg, rationale for including, correlative endpoint, time points recommended): 7. Independent of the geriatric assessment, are there other core measures included for this study regarding comorbidity, or baseline blood work that should be collected? ◻ Yes, what are they? ◻ No, I recommend that the following core measures be considered: 8. Has the study team already engaged someone from the Cancer in the Older Adult Committee in designing this study? ◻ Yes (Name __________________________) ◻ No ◻ N/A I don’t think this is necessary.b 9. If this concept is approved for protocol development (and it is appropriate to add a committee member to the study team), would you be willing to serve as the Cancer in the Older Adult co-chair for this study? ◻ Yes. ◻ No, please provide a recommendation for a Cancer in the Older Adult Co-Chair: ◻ No, Older Adult Committee member not necessary. Additional comments for study team consideration: CANCER IN OLDER ADULT COMMITTEE CHECKLIST FOR STUDY CONCEPT REVIEW Reviewed by Date: 1. Is this concept applicable to older patients with cancer (≥65 years of age)? ◻ Yes, proceed to next question. ◻ No, your review is complete and the rest of the form does not need to be completed. Additional comments for consideration: 2. Is there an upper age limit on this concept (and/or is Inclusion Across the Lifespan addressed in this concept)? ◻ No. ◻ Yes, the upper age limit is appropriate for this concept and rationale for the age cut-off is provided. ◻ Yes, the upper age limit is appropriate for this concept; however, a rationale for the age cut-off is not provided and needs to be included. ◻ Yes, the upper age limit is NOT appropriate for this concept. Please explain your concerns and provide recommendations: Note: If possible/relevant, please provide a reference(s) to support your recommendation: 3. Are inclusion criteria appropriate and as broad as possible with respect to enrolling older patients with cancer? ◻ Yes, no changes recommended. ◻ No, explain your concerns and provide recommendation: 4. Are endpoints relevant to older adults with cancer (such as the impact of treatment on function) already included in this concept? ◻ Yes, skip the next question. ◻ No, but this is not relevant to this concept. ◻ No, please consider the following endpoints relevant to older adults with cancer (comments below). Comments and recommendations: 5. Are there measures to ensure that sufficient numbers of older patients are enrolled to the study (ie, proportions of older patients enrolled reflect the proportions in the population?)a ◻ Yes, not applicable, this study is dedicated to older patients with cancer. ◻ Yes, the study design specifies the number of older patients with cancer that will need to be enrolled. ◻ Yes, other, explain. ◻ No, not applicable to this study. ◻ No, I would recommend adequate numbers of older patients be enrolled to this study. Please provide details for this recommendation: 6. Is the geriatric assessment included? ◻ Yes. ◻ No, I do not recommend that the geriatric assessment be included. ◻ No, I recommend that the geriatric assessment be included. Please provide details for this recommendation (eg, rationale for including, correlative endpoint, time points recommended): 7. Independent of the geriatric assessment, are there other core measures included for this study regarding comorbidity, or baseline blood work that should be collected? ◻ Yes, what are they? ◻ No, I recommend that the following core measures be considered: 8. Has the study team already engaged someone from the Cancer in the Older Adult Committee in designing this study? ◻ Yes (Name __________________________) ◻ No ◻ N/A I don’t think this is necessary.b 9. If this concept is approved for protocol development (and it is appropriate to add a committee member to the study team), would you be willing to serve as the Cancer in the Older Adult co-chair for this study? ◻ Yes. ◻ No, please provide a recommendation for a Cancer in the Older Adult Co-Chair: ◻ No, Older Adult Committee member not necessary. Additional comments for study team consideration: a Trials should include an analysis of relevant endpoints in those aged 65 years and older that is powered to identify the differences between those endpoints. b If N/A or not necessary are checked, an explanation should be given to explain why. Open in new tab Standard language for site training and caregiver materials is also recommended. A relevant model is the Common Terminology Criteria for Adverse Events and Patient Reported Outcomes protocol template (https://healthcaredelivery.cancer.gov/pro-ctcae/measurement.html). Third, because it is well recognized that older adults are underrepresented in cancer clinical trials, specific plans to recruit this population, with standard operating procedures, should be developed and required for trials specific to older adults and trials for which older adults are eligible. This resource specific to older cancer patients will provide investigators with expert-developed resources to improve quality and reduce duplicative efforts around research and enrollment of older adults. Lastly, we recommend that there be centralized support from experts in geriatric ocology that can be leveraged locally. One potential resource is the Cancer in Aging Research Group (CARG; mycarg.org). CARG is the largest organization for cancer and aging scholars in North America and is support by an National Institute on Aging infrastructure grant (5R33AG059206) to make resources available, allowing a mechanism to submit inquiries, find expertise, receive analytic input, and obtain aging-specific expert feedback. Other organizations, such as the International Society of Geriatric Oncology, American Society for Clinical Oncology, the American Geriatrics Society, and the Association of Community Cancer Centers, are also available to provide input. Harmonizing resources across such groups would be valuable. The availability of these centralized resources for concept and protocol development and of consultants with expertise in geriatrics and geriatric oncology would provide investigators with the means to optimally enroll and treat older patients in cancer clinical trials. Still, there are several unanswered questions regarding these resources. We realize that as systems continue to change, ongoing evaluation and improvement will be necessary to make sure that key resources are readily available and harmonized across groups. There is also the concern regarding the storage and updating of these resources to maintain wide availability. Because cancer in older adults is a global health issue, not a local or even national one, the institution that is responsible for maintaining the resources should be one that not only makes them widely available but ensures they are multilingual and culturally sensitive as well. Furthermore, regular vetting of the existing resources and the uptake of new ones must be conducted to ensure accuracy, quality, and appropriate use. Such monitoring would provide feedback that will lead to resource updates, based on utilization and what modifications are deemed necessary to make accrual successful in various settings. Most importantly, we recognize the importance of access and equitable dissemination. Champions will be needed to spread the word about the availability of these resources and to encourage use. Then, a system will need to be developed to make adjustments to monitor implementation and facilitate use. Such coordination requires underlying infrastructure, including expertise, transparent processes, and high-quality vetting processes. Recommendation 2: Training for Clinical Research Staff Current guideline recommendations are that geriatric assessment (GA) be standard of care in all older patients with cancer starting on systemic therapy (18-20); the uptake of this practice is low. In a recent international survey of oncology providers, only 20% reported routinely employing a GA in the management of their older patients considering chemotherapy (21). Furthermore, there is no consensus on the appropriate way to approach this assessment, whether by screening for problems and referring only some patients for comprehensive GA (CGA) or by having CGA, or certain portions of the CGA, done in all older adults with cancer. In addition, there has been limited formal training for performing GA across all clinical and research sites, which results in variability in instrument selection and scoring (missing data). One way to address the low uptake of GA inclusion in trials is to provide better training for staff for obtaining the GA. Although this does not immediately solve the concern about use of the GA results, it may provide greater consistency in the data collection. An example of the effective use of GA training comes from the Alliance for Cancer Clinical Trials. The Cancer in Older Adults Committee for the Alliance developed and pilot-tested a cancer-specific GA for use in its clinical trials (22,23). In partnership with policies to require its use, along with training in the use of the GA, broader uptake has occurred. The CARG also compiled data from using an abbreviated CGA in older patients with cancer and developed a tool by which chemotherapy toxicity is accurately predicted (24-26). This tool has now been incorporated into intervention trials and is available for public use through the CARG website. Another example of use of GA in research comes from a cluster-randomized clinical trial from the NCORP who studied the use of GA in oncology visits and found that communication about aging-related concerns was improved (27). Further development of training materials, whether video or printed, can maximize the widespread use of the GA in more locations without needing additional staff. We, therefore, recommend that GA training be delivered to research staff online and that the completion of the training be tracked. One possible format would be through the NCI learning management system. Standardization of GA training will also help identify processes that can be improved and streamlined. The target audience for this training will include, but not be limited to, principal investigators, clinical research professionals, and others administering the GA. Availability of centralized training would also allow consistent training to reduce duplication of work for sites and groups and improve data collection and quality. Key GA training needs should be analyzed, identified, and tracked, which will require an ongoing evaluation process. Recommendation 3: Development of CDEs The plethora of different GA tools and the lack of consensus on their use creates challenge in designing trials. In addition, there is confusion about whether the GA should be performed as a pretreatment evaluation to gather baseline data or as an outcome measure. It is important that data elements, or variables, whether for baseline assessment or for outcome measurement, be carefully defined and consistently collected in clinical research. These elements, including GA specific items, are important for defining trial eligibility, developing intervention, guiding on-trial monitoring and data collection, and reporting study outcomes. The data elements uniquely important in older patients with cancer include geriatric syndromes, as defined by a GA, and other issues especially important to older patients, such as vision and hearing deficits. As a starting point, we suggest that the GA be used to structure CDEs for cancer clinical trials for older adults. The domains of the GA, including functional status, comorbidity, cognitive function, nutrition, psychological state and social support, and polypharmacy, are well established (28). Assessment of each has been defined by multiple and various measures, and only some of these have been specifically studied in populations of older patients with cancer. There are multiple forms of GA, including mailed, self-administered, electronic, collected from administrative databases, clinician assessed, and others. Some have been validated in patients with cancer and some in only certain types of cancers. As a result, data reporting is highly variable. Similar or identical GA items are often being collected in separate study databases. There is inconsistency in data descriptors, which makes it extremely difficult to aggregate and manage aging-related data across studies. We, therefore, recommend standardization of GA data nomenclature for the reporting of NCI trials. One possibility is for work to be done with NCI to add CDEs for key GA items to the NCI CDE browser for use in future NCTN and NCORP trial case report forms. For these new items, we will need to work with statisticians and data managers to develop electronic case report forms for key GA tools that can be adapted by individual groups and research bases. The advantages of this approach will be the reduction in duplication of effort and improved efficiency. It will also encourage consistent centralized data collection to facilitate aggregate analyses. There are remaining questions about the feasibility of collecting GA data in trials and whether it is feasible to have clinical research professionals input the data into the Medidata Rave Electronic Data Capture (RAVE) system or other data capturing systems. Ongoing evaluation of the process will help define other ways to facilitate collection and analysis of GA data in NCTN and NCORP trials. Recommendation 4: Evaluation of Enrollment Interventions A likely reason for the lack of improvement in enrollment of older adults in cancer clinical trials is failure to systematically study interventions to improve accrual. We realize that it is difficult to implement change in systems, especially across all NCTN and NCORP trials. We therefore recommend a strategic approach that first assesses the current landscape, evaluates what has led to successful accrual of older adults to clinical trials, and develops targeted interventions in disease areas that are struggling to enroll older adults. Assessment of our current status is available in the literature (13). There are some examples in the literature of studies that were successful in accruing older adults, such as those that were specific to older adults (29) and those that include cancer types and treatments pertinent to older adults. Trials for older adults can be pragmatic and performed in the community. Dr Mohile and colleagues demonstrated what is possible with their cluster randomized intervention trial in adults aged older than 70 years with at least 1 deficit on a GA across 31 community oncology clinics in the NCORP (30). This large trial of more than 700 patients showed that use of a GA-guided intervention reduced chemotherapy-related grade 3-5 toxicity in vulnerable older adults with advanced cancer. The methods used to recruit and enroll such patients (and their families) can serve as a model for others. Older adult-specific trials have also been successful in incorporating relevant assessments, including the GA. In a chronic lymphocytic leukemia phase III treatment trial testing first-line ibrutinib or ibrutinib with rituximab vs chemo-immunotherapy in patients aged 65 years or older, 74% of the 547 patients consented to have the GA done, of which 95% completed the baseline GA (31). In another trial, a phase II study of first-line sorafenib and chemotherapy in patients aged 60 years or older with acute myeloid leukemia, 80% of patients consented to the GA and 93% of these patients completed the baseline GA (32). Again, this demonstrates that trials designed for older adults can successfully incorporate relevant aging-related endpoints. Another opportunity to use infrastructure to make trials more relevant to older patients with cancer is to design trials to test enrollment in GA-guided intervention studies. An example of such intervention-based trial designs is differential dosing studies in which lower doses of cancer therapies are tested against standard doses. There have been several examples of successfully conducted studies in older adults with colon, ovarian, and gastric cancer where investigators tested the efficacy and safety of reduced intensity treatment (33-35). Another approach is to allow trial designs that are specifically adapted to older adults. Examples of such adapted clinical trial advances include studies where therapies are adjusted (intensified or de-intensified) according to frailty metrics (36). Although the results from these studies differ across diseases and populations, this type of study design represents a critical opportunity for investigating the optimal delivery of cancer treatment in older adults. Such interventional trial designs require changes in policies and procedures, which are crucial aspects of infrastructure. Moving beyond GA, we recommend iterative clinical trial design based on lessons learned from other investigators collated in the proposed centralized resource. Investigators, groups, and sites who have demonstrated success in accrual of older adults should be queried about their methods and insights into the problem. Then, we can utilize these lessons learned to inform design and recruitment and/or retention of other studies, thus leading to specific interventions to improve accrual in disease areas that are struggling to enroll older adults. By using a targeted approach and learning from what works and what does not, we can develop new approaches. This will help us pilot new ideas, show feasibility, and enhance future broad implementation. To evaluate the success of this approach, we will need to define successful, low, and high enrollment of older adults to NCTN and NCORP trials. Priorities will also need to be set, such that the areas of greatest need are targeted. Discussion In summary, a multipronged approach toward improving infrastructure, which includes people, processes, and policies, is warranted to potentially improve recruitment, enrollment, and accrual of older patients into cancer clinical trials. Addressing infrastructural barriers is a critical priority to remove key barriers to clinical trial accrual. This includes 1) centralizing existing resources and expertise; 2) training clinical research staff in use of the GA; 3) developing CDEs to increase knowledge; and 4) evaluating which interventions are most effective. Such infrastructure changes, in coordination, could function as a recruitment core resource on a national level to important scientific questions relevant for older adults. These actionable changes can be made in the near future and, in combination with other approaches described elsewhere in this issue of the journal, can make meaningful differences toward improving enrollment of older adults. We hope that these initial resources help lay the foundation for additional changes. Recognizing that this is a start to a much larger program of change, these meaningful changes to existing infrastructure set the stage for a broader, coordinated approach to the accrual of older adults. As we think about the future, we should consider how to restructure our approach to interventional clinical research, to embed aging concerns as a focus, and to ensure that older adults, in whom cancer is most common, are not left behind as the therapeutic options expand. We need to plant the seeds of a more inclusive clinical trial system that considers the needs of older adults and is inclusive of all vulnerable patients. Rather than ask patients and families to adapt to our system, we should be designing a recruitment system to best accommodate the needs of our older adult patients. Funding The workshop was coordinated by the National Cancer Institute Division of Cancer Prevention in collaboration with the Division of Cancer Treatment and Diagnosis. Writing of this manuscript was not funded. National Cancer Institute staff provided minor edits to the final manuscript. Notes Disclosures: Authors have nothing directly related to the manuscript to disclose. Author contributions: Drs Kimmick and Sedrak composed the summary of this part of the symposium; Dr Dale helped organize the symposium, oversee the agenda, and summarize the findings; all authors reviewed and approved the manuscript. Acknowledgements: We acknowledge the leadership and support from the Cancer and Aging Research Group for their role in supporting this work. Disclaimers: None. Prior presentations: This manuscript is the summary from the Infrastructure Working Group from “Engaging Older Adults in the NCI Clinical Trails Network: Challenges and Opportunities,” a workshop held April 26-27, 2021. 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Infrastructure to Support Accrual of Older Adults to National Cancer Institute Clinical Trials

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Oxford University Press
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Copyright © 2022 Oxford University Press
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1052-6773
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Abstract

Abstract As part of ongoing efforts to meaningfully improve recruitment, enrollment, and accrual of older adults into cancer clinical trials, the National Cancer Institute (NCI) sponsored a workshop with experts across the country entitled Engaging Older Adults in the NCI Clinical Trials Network: Challenges and Opportunities. Three working groups, including Study Design, Infrastructure, and Stakeholders, were formed, who worked together to offer synergistic improvements in the system. Here, we summarize the workshop discussions of the Infrastructure Working Group, whose goal was to address infrastructural challenges, identify underlying resources, and offer solutions to facilitate accrual of older adults into cancer clinical trials. Based on preconference work and workshop discussions, four key recommendations to strengthen NCI infrastructure were proposed: 1) further centralize resources and expertise; 2) provide training for clinical research staff; (3) develop common data elements; and 4) evaluate what works and does not work. These recommendations provide a strategy to improve the infrastructure to enroll more older adults in cancer clinical trials. The foundation for evidence-based guidelines in cancer care stems from evidence gained in a variety of studies, especially high-quality clinical trials. Yet, although more than half of patients with cancer are aged 65 years and older, historically, only about a quarter of patients enrolled in cancer clinical trials are in this age group (1,2). Barriers and challenges to the recruitment, enrollment, and accrual of older adults to clinical trials are multifaceted, complex, and remarkably persistent. They broadly include issues stemming from those that are physician-, caregiver-, and patient-related as well as from the medical and research system overall (3-9). In a recent systematic literature review focused on interventions to increase accrual of older adults to cancer clinical trials, only 13 high-quality studies were identified, with high quality defined as articles that were 1) empirical; 2) peer reviewed; 3) experimental, quasi-experimental, or observational; 4) evaluating barriers to participation and/or interventions to improve the participation of older adults; and 5) focused on patients aged 65 years and older with cancer (10). Most concerning, only 1 prospective randomized trial meeting these criteria was identified, and it was a negative trial (11). The systematic review highlighted the paucity of high-quality evidence that uniformly and comprehensively define barriers to cancer clinical trial accrual of older adults and found no evidence identifying effective interventions to improve enrollment of older adults. There is clearly much work left to be done. Reference to this need is made in the National Institutes of Health Central Resources for Grants and Funding Information (https://grants.nih.gov/policy/inclusion/lifespan.htm) and was recently highlighted by an expert perspective (12). In this report, we focus on the role of infrastructure in clinical trials, describe its role in the current situation and offer ways to improve that infrastructure in future trial design. It is helpful in this context to clearly state what we mean by infrastructure. Infrastructure, in this context, means the people, processes, and policies that underlie the conduct of clinical trials research. This differs from the larger considerations of structure of the entire research enterprise, both within the National Cancer Institute (NCI) and outside of it, which governs many aspects of research but is outside the scope here. This specific report, based on the conference, is focused on infrastructure, which is a component within the larger structure. Improving accrual of older adults to clinical trials will require strategic intervention at multiple levels, including the individuals involved and the infrastructural components. Importantly, the larger and most critical barriers are at the infrastructural level. How do we know this? First, certain characteristics of older adults with cancer constitute important barriers. Studies show that more than half of patients are willing to participate in clinical trials when offered (13) and that older patients are as likely as younger patients to participate (14). In fact, 3 of 4 patients with cancer will not have the opportunity to participate in a clinical trial because there is no trial available locally or they are ineligible (13,15,16). These difficulties are common for all adult patients with cancer, but are even more amplified for vulnerable groups, including the older adults. Given this, specific interventions to improve accrual must be developed, and those interventions will need to be infused into the trial designs. Trials themselves will need careful attention to this design, including broader eligibility criteria and clearer definitions of outcome measures that are more appropriate for older adults, to allow for the inclusion of as many older patients as possible. In addition, the underlying infrastructure, described below, must facilitate the participation of older adults, such that their accrual is actively pursued, breaking down the inertia of the current structures, encouraging the consistent collection of information pertinent to their needs, and offering training to staff on these needs. We should also study ways to improve the enrollment with high-quality research designs that allow greater opportunity for older adults to enroll in trials specific to their needs. Of course, infrastructure changes are only one aspect of the solution; other concerns are addressed in the companion articles in this issue. Conference Structure and Goals, Infrastructure Subgroup Coordinated by the NCI Division of Cancer Prevention in collaboration with the Division of Cancer Treatment and Diagnosis, and supported by the Cancer MoonshotSM Network for Direct Patient Engagement Implementation Team, a virtual workshop entitled Engaging Older Adults in the NCI Clinical Trials Network: Challenges and Opportunities was held April 26-27, 2021, to jump-start initiatives that will hopefully lead to improved accrual of older adult patients to cancer clinical trials. In preparation for the workshop, working groups centering on study design, infrastructure, and stakeholders were formed and met in advance to create an agenda and facilitate synergies across groups. In this paper, we describe the recommendations made by the Infrastructure Working Group, based on that agenda and the focused discussions during the conference among the members of this group who are co-authors of this manuscript. Organizers agreed that a focused approach would most likely lead to near-future changes, and the subgroups focused on actionable changes. The charge to the Infrastructure Working Group, developed in advance of the conference, is outlined in Table 1. The group focus was to address underlying resources needed to facilitate accrual and gather pertinent data specific for older adults with cancer—in other words, to suggest ways to alter current infrastructure for clinical trials that meaningfully change the core elements of people, processes, and policies that would improve recruitment, enrollment, and accrual and would standardize assessments and results across trials. Our goal was to identify achievable opportunities in the near-term, or actionable “low-hanging fruit,” within an already strong system that would strengthen the National Clinical Trials Network (NCTN) and NCI Community Oncology Research Program (NCORP) infrastructure and specifically address the barriers and challenges to engagement of older adults, families, and providers in NCI-sponsored clinical trials. Although this scope is narrow, given the many challenges faced in changing practices and influencing existing infrastructure, it is also targeted and important. For example, it focuses on the issues for older adults, one vulnerable group among many, and only indirectly benefits other vulnerable groups impacted by biased infrastructure including race, ethnicity, and gender, to name a few. This is not to diminish the importance of those groups, only to acknowledge the agenda established for this workshop and group, and it reflects the overall goal of decreasing age bias. Table 1. Charge to the Infrastructure Working Group Task . Charge . 1. Develop a roadmap from conceptualization of research question to dissemination of results, including Identification of necessary resources Consideration of the older adult throughout the process Inclusion of a recruitment plan 2. Describe resources available to investigators explaining they can access experts with aging expertise 3. Define infrastructure needs to perform comprehensive geriatric assessment 4. Describe use of technology or telehealth to engage older adults in clinical research 5. Consider approaches to accrue racial and ethnic minority older adults and those from rural areas 6. Develop a plan for the evaluation of what has worked and not worked Task . Charge . 1. Develop a roadmap from conceptualization of research question to dissemination of results, including Identification of necessary resources Consideration of the older adult throughout the process Inclusion of a recruitment plan 2. Describe resources available to investigators explaining they can access experts with aging expertise 3. Define infrastructure needs to perform comprehensive geriatric assessment 4. Describe use of technology or telehealth to engage older adults in clinical research 5. Consider approaches to accrue racial and ethnic minority older adults and those from rural areas 6. Develop a plan for the evaluation of what has worked and not worked Open in new tab Table 1. Charge to the Infrastructure Working Group Task . Charge . 1. Develop a roadmap from conceptualization of research question to dissemination of results, including Identification of necessary resources Consideration of the older adult throughout the process Inclusion of a recruitment plan 2. Describe resources available to investigators explaining they can access experts with aging expertise 3. Define infrastructure needs to perform comprehensive geriatric assessment 4. Describe use of technology or telehealth to engage older adults in clinical research 5. Consider approaches to accrue racial and ethnic minority older adults and those from rural areas 6. Develop a plan for the evaluation of what has worked and not worked Task . Charge . 1. Develop a roadmap from conceptualization of research question to dissemination of results, including Identification of necessary resources Consideration of the older adult throughout the process Inclusion of a recruitment plan 2. Describe resources available to investigators explaining they can access experts with aging expertise 3. Define infrastructure needs to perform comprehensive geriatric assessment 4. Describe use of technology or telehealth to engage older adults in clinical research 5. Consider approaches to accrue racial and ethnic minority older adults and those from rural areas 6. Develop a plan for the evaluation of what has worked and not worked Open in new tab With this scope and focus in mind, the Infrastructure Working Group made 4 key recommendations to strengthen infrastructure, described in greater detail below: 1) increase centralization of resources and expertise; 2) greater training for clinical research staff; 3) emphasis on developing common data elements (CDEs) to be used across studies; and 4) systematic evaluation of interventions to learn which interventions work best. These recommended solutions, anticipated gains, and other questions for discussion are outlined in Table 2 and discussed below. Two of the areas for improvement identified in advance of the conference—greater use of technology and intersectionality considerations of race and ethnicity and rural areas—received less direct emphasis and are embedded in the existing recommendations. Table 2. Improving cancer clinical trial accrual in older adults, recommendations from the Infrastructure Working Group . Problem . Solution . Gain . Discussion . Centralize resources and expertise Investigators do not have centralized geriatric oncology resources or access to local expertise. Develop and centralize resources: “Checklist” for concept development “Recruitment plans” (roadmap) Example protocol language Referral for support via CARinG R33 infrastructure Providing investigators with expert-developed resources and improving quality and reducing duplicative efforts around research and enrollment of older adults What resources would be most helpful? Where should these resources be housed? Can we monitor uptake of these resources? How can we encourage and/or facilitate use? How can we ensure implementation? Train clinical research staff No formal training of GA across all sites. This results in variability in instrument completion and scoring (missing data). Develop and centralize GA training: Deliver it online Track site completion Consistent training can reduce duplication of work for sites and groups and improve data collection and quality What are key GA training needs that can be addressed through online training? Develop CDEs Similar or identical GA items are often being collected in separate study databases. Inconsistency in data descriptors. Difficult to aggregate and manage aging-related data across studies. Standardize GA data nomenclature for reporting of NCI trials: Work with NCI to add CDEs for key GA items to the NCI CDE browser for use in future NCTN-NCORP trial case report forms Work with statisticians and data managers to develop Rave case report forms for key GA tools that could be adapted by individual groups and research bases Reduce duplication of effort, increase efficiency Encourage consistent centralized data collection to facilitate aggregate analyses Is it feasible to collect GA data on trials and have clinical research associates input the data in Rave? What else could be done to make it easier to collect and analyze GA data in NCTN–NCORP trials? Evaluate what works and what does not work It is difficult to implement change across all NCTN-NCORP trials. Strategic approach: Assess the current landscape Learn from diseases that are successful at enrolling older adults (high rates); meet with successful investigators and sites Target specific interventions in disease areas that are struggling to enroll older adults Using a targeted approach and learning from what works and what does not will help us pilot new ideas, show feasibility, and enhance future broad implementation How do we define successful, low, and high enrollment of older adults to NCTN-NCORP trials? What disease areas should be targeted? . Problem . Solution . Gain . Discussion . Centralize resources and expertise Investigators do not have centralized geriatric oncology resources or access to local expertise. Develop and centralize resources: “Checklist” for concept development “Recruitment plans” (roadmap) Example protocol language Referral for support via CARinG R33 infrastructure Providing investigators with expert-developed resources and improving quality and reducing duplicative efforts around research and enrollment of older adults What resources would be most helpful? Where should these resources be housed? Can we monitor uptake of these resources? How can we encourage and/or facilitate use? How can we ensure implementation? Train clinical research staff No formal training of GA across all sites. This results in variability in instrument completion and scoring (missing data). Develop and centralize GA training: Deliver it online Track site completion Consistent training can reduce duplication of work for sites and groups and improve data collection and quality What are key GA training needs that can be addressed through online training? Develop CDEs Similar or identical GA items are often being collected in separate study databases. Inconsistency in data descriptors. Difficult to aggregate and manage aging-related data across studies. Standardize GA data nomenclature for reporting of NCI trials: Work with NCI to add CDEs for key GA items to the NCI CDE browser for use in future NCTN-NCORP trial case report forms Work with statisticians and data managers to develop Rave case report forms for key GA tools that could be adapted by individual groups and research bases Reduce duplication of effort, increase efficiency Encourage consistent centralized data collection to facilitate aggregate analyses Is it feasible to collect GA data on trials and have clinical research associates input the data in Rave? What else could be done to make it easier to collect and analyze GA data in NCTN–NCORP trials? Evaluate what works and what does not work It is difficult to implement change across all NCTN-NCORP trials. Strategic approach: Assess the current landscape Learn from diseases that are successful at enrolling older adults (high rates); meet with successful investigators and sites Target specific interventions in disease areas that are struggling to enroll older adults Using a targeted approach and learning from what works and what does not will help us pilot new ideas, show feasibility, and enhance future broad implementation How do we define successful, low, and high enrollment of older adults to NCTN-NCORP trials? What disease areas should be targeted? a CDE = common data element; GA = geriatric assessment; NCI = National Cancer Institute; NCTN-NCORP = National Clinical Trials Network–NCI Community Oncology Research Program. Open in new tab Table 2. Improving cancer clinical trial accrual in older adults, recommendations from the Infrastructure Working Group . Problem . Solution . Gain . Discussion . Centralize resources and expertise Investigators do not have centralized geriatric oncology resources or access to local expertise. Develop and centralize resources: “Checklist” for concept development “Recruitment plans” (roadmap) Example protocol language Referral for support via CARinG R33 infrastructure Providing investigators with expert-developed resources and improving quality and reducing duplicative efforts around research and enrollment of older adults What resources would be most helpful? Where should these resources be housed? Can we monitor uptake of these resources? How can we encourage and/or facilitate use? How can we ensure implementation? Train clinical research staff No formal training of GA across all sites. This results in variability in instrument completion and scoring (missing data). Develop and centralize GA training: Deliver it online Track site completion Consistent training can reduce duplication of work for sites and groups and improve data collection and quality What are key GA training needs that can be addressed through online training? Develop CDEs Similar or identical GA items are often being collected in separate study databases. Inconsistency in data descriptors. Difficult to aggregate and manage aging-related data across studies. Standardize GA data nomenclature for reporting of NCI trials: Work with NCI to add CDEs for key GA items to the NCI CDE browser for use in future NCTN-NCORP trial case report forms Work with statisticians and data managers to develop Rave case report forms for key GA tools that could be adapted by individual groups and research bases Reduce duplication of effort, increase efficiency Encourage consistent centralized data collection to facilitate aggregate analyses Is it feasible to collect GA data on trials and have clinical research associates input the data in Rave? What else could be done to make it easier to collect and analyze GA data in NCTN–NCORP trials? Evaluate what works and what does not work It is difficult to implement change across all NCTN-NCORP trials. Strategic approach: Assess the current landscape Learn from diseases that are successful at enrolling older adults (high rates); meet with successful investigators and sites Target specific interventions in disease areas that are struggling to enroll older adults Using a targeted approach and learning from what works and what does not will help us pilot new ideas, show feasibility, and enhance future broad implementation How do we define successful, low, and high enrollment of older adults to NCTN-NCORP trials? What disease areas should be targeted? . Problem . Solution . Gain . Discussion . Centralize resources and expertise Investigators do not have centralized geriatric oncology resources or access to local expertise. Develop and centralize resources: “Checklist” for concept development “Recruitment plans” (roadmap) Example protocol language Referral for support via CARinG R33 infrastructure Providing investigators with expert-developed resources and improving quality and reducing duplicative efforts around research and enrollment of older adults What resources would be most helpful? Where should these resources be housed? Can we monitor uptake of these resources? How can we encourage and/or facilitate use? How can we ensure implementation? Train clinical research staff No formal training of GA across all sites. This results in variability in instrument completion and scoring (missing data). Develop and centralize GA training: Deliver it online Track site completion Consistent training can reduce duplication of work for sites and groups and improve data collection and quality What are key GA training needs that can be addressed through online training? Develop CDEs Similar or identical GA items are often being collected in separate study databases. Inconsistency in data descriptors. Difficult to aggregate and manage aging-related data across studies. Standardize GA data nomenclature for reporting of NCI trials: Work with NCI to add CDEs for key GA items to the NCI CDE browser for use in future NCTN-NCORP trial case report forms Work with statisticians and data managers to develop Rave case report forms for key GA tools that could be adapted by individual groups and research bases Reduce duplication of effort, increase efficiency Encourage consistent centralized data collection to facilitate aggregate analyses Is it feasible to collect GA data on trials and have clinical research associates input the data in Rave? What else could be done to make it easier to collect and analyze GA data in NCTN–NCORP trials? Evaluate what works and what does not work It is difficult to implement change across all NCTN-NCORP trials. Strategic approach: Assess the current landscape Learn from diseases that are successful at enrolling older adults (high rates); meet with successful investigators and sites Target specific interventions in disease areas that are struggling to enroll older adults Using a targeted approach and learning from what works and what does not will help us pilot new ideas, show feasibility, and enhance future broad implementation How do we define successful, low, and high enrollment of older adults to NCTN-NCORP trials? What disease areas should be targeted? a CDE = common data element; GA = geriatric assessment; NCI = National Cancer Institute; NCTN-NCORP = National Clinical Trials Network–NCI Community Oncology Research Program. Open in new tab Recommendation 1: Centralization of Resources and Expertise A major challenge for clinical trial enrollment of older adults is the national paucity of expertise. Investigators typically do not have centralized geriatric oncology resources or access to local expertise. For instance, in a survey of NCORP, among 943 NCORP practices, only 2% had a fellowship-trained geriatric oncologist on staff and 37% had geriatricians available for consultation or co-management, and of those, only 13% (5% overall) had geriatricians available in the oncology clinic (17). This not only hinders care for older adults but also has implications for clinical trial accrual and available expertise for trial design. Given that this situation is unlikely to change quickly, another solution is needed. Leveraging existing resources more efficiently is one way to approach this problem. To improve resources to specifically address the unique issues that are faced by older adults with cancer and to improve accrual to clinical trials, we propose that existing national resources be further developed and targeted for this group. Furthermore, resources should be centralized, organized, and made known and accessible to health-care professionals. An additional benefit would be the impact on all patients, regardless of age, who face similar barriers of access because of shared vulnerabilities. Recommendations suggested by the Infrastructure Working Group to augment available resources are listed in Table 2. Where possible, we suggested that currently available resources be leveraged so that they can be quickly deployed. Examples are offered that can be readily adapted and applied to older adults. First, we recommend that checklists be developed and followed during clinical trial concept development and, second, we suggest that examples for standard protocol language be made available. The NCTN Adolescent and Young Adult checklist for concepts and protocols (https://ctep.cancer.gov/protocolDevelopment/docs/NCTN_AYA_Checklist_for_Concepts_and_Protocols.pdf) is an example of a successful checklist. This document provides checklists for concept stage and protocol stages of trial development and provides standardized protocol language regarding study rationale, measures, and statistical design. Another checklist, focused on older adults, has been developed for the Alliance’s Cancer in Older Adult Committee for Study Concept Review (Table 3). Such checklists provide policies and processes to ensure consistency and quality, and they could be more widely adapted across the NCI. Table 3. The Alliance’s Cancer in Older Adult Committee Check List for Study Concept Review CANCER IN OLDER ADULT COMMITTEE CHECKLIST FOR STUDY CONCEPT REVIEW Reviewed by Date: 1. Is this concept applicable to older patients with cancer (≥65 years of age)? ◻ Yes, proceed to next question. ◻ No, your review is complete and the rest of the form does not need to be completed. Additional comments for consideration: 2. Is there an upper age limit on this concept (and/or is Inclusion Across the Lifespan addressed in this concept)? ◻ No. ◻ Yes, the upper age limit is appropriate for this concept and rationale for the age cut-off is provided. ◻ Yes, the upper age limit is appropriate for this concept; however, a rationale for the age cut-off is not provided and needs to be included. ◻ Yes, the upper age limit is NOT appropriate for this concept. Please explain your concerns and provide recommendations: Note: If possible/relevant, please provide a reference(s) to support your recommendation: 3. Are inclusion criteria appropriate and as broad as possible with respect to enrolling older patients with cancer? ◻ Yes, no changes recommended. ◻ No, explain your concerns and provide recommendation: 4. Are endpoints relevant to older adults with cancer (such as the impact of treatment on function) already included in this concept? ◻ Yes, skip the next question. ◻ No, but this is not relevant to this concept. ◻ No, please consider the following endpoints relevant to older adults with cancer (comments below). Comments and recommendations: 5. Are there measures to ensure that sufficient numbers of older patients are enrolled to the study (ie, proportions of older patients enrolled reflect the proportions in the population?)a ◻ Yes, not applicable, this study is dedicated to older patients with cancer. ◻ Yes, the study design specifies the number of older patients with cancer that will need to be enrolled. ◻ Yes, other, explain. ◻ No, not applicable to this study. ◻ No, I would recommend adequate numbers of older patients be enrolled to this study. Please provide details for this recommendation: 6. Is the geriatric assessment included? ◻ Yes. ◻ No, I do not recommend that the geriatric assessment be included. ◻ No, I recommend that the geriatric assessment be included. Please provide details for this recommendation (eg, rationale for including, correlative endpoint, time points recommended): 7. Independent of the geriatric assessment, are there other core measures included for this study regarding comorbidity, or baseline blood work that should be collected? ◻ Yes, what are they? ◻ No, I recommend that the following core measures be considered: 8. Has the study team already engaged someone from the Cancer in the Older Adult Committee in designing this study? ◻ Yes (Name __________________________) ◻ No ◻ N/A I don’t think this is necessary.b 9. If this concept is approved for protocol development (and it is appropriate to add a committee member to the study team), would you be willing to serve as the Cancer in the Older Adult co-chair for this study? ◻ Yes. ◻ No, please provide a recommendation for a Cancer in the Older Adult Co-Chair: ◻ No, Older Adult Committee member not necessary. Additional comments for study team consideration: CANCER IN OLDER ADULT COMMITTEE CHECKLIST FOR STUDY CONCEPT REVIEW Reviewed by Date: 1. Is this concept applicable to older patients with cancer (≥65 years of age)? ◻ Yes, proceed to next question. ◻ No, your review is complete and the rest of the form does not need to be completed. Additional comments for consideration: 2. Is there an upper age limit on this concept (and/or is Inclusion Across the Lifespan addressed in this concept)? ◻ No. ◻ Yes, the upper age limit is appropriate for this concept and rationale for the age cut-off is provided. ◻ Yes, the upper age limit is appropriate for this concept; however, a rationale for the age cut-off is not provided and needs to be included. ◻ Yes, the upper age limit is NOT appropriate for this concept. Please explain your concerns and provide recommendations: Note: If possible/relevant, please provide a reference(s) to support your recommendation: 3. Are inclusion criteria appropriate and as broad as possible with respect to enrolling older patients with cancer? ◻ Yes, no changes recommended. ◻ No, explain your concerns and provide recommendation: 4. Are endpoints relevant to older adults with cancer (such as the impact of treatment on function) already included in this concept? ◻ Yes, skip the next question. ◻ No, but this is not relevant to this concept. ◻ No, please consider the following endpoints relevant to older adults with cancer (comments below). Comments and recommendations: 5. Are there measures to ensure that sufficient numbers of older patients are enrolled to the study (ie, proportions of older patients enrolled reflect the proportions in the population?)a ◻ Yes, not applicable, this study is dedicated to older patients with cancer. ◻ Yes, the study design specifies the number of older patients with cancer that will need to be enrolled. ◻ Yes, other, explain. ◻ No, not applicable to this study. ◻ No, I would recommend adequate numbers of older patients be enrolled to this study. Please provide details for this recommendation: 6. Is the geriatric assessment included? ◻ Yes. ◻ No, I do not recommend that the geriatric assessment be included. ◻ No, I recommend that the geriatric assessment be included. Please provide details for this recommendation (eg, rationale for including, correlative endpoint, time points recommended): 7. Independent of the geriatric assessment, are there other core measures included for this study regarding comorbidity, or baseline blood work that should be collected? ◻ Yes, what are they? ◻ No, I recommend that the following core measures be considered: 8. Has the study team already engaged someone from the Cancer in the Older Adult Committee in designing this study? ◻ Yes (Name __________________________) ◻ No ◻ N/A I don’t think this is necessary.b 9. If this concept is approved for protocol development (and it is appropriate to add a committee member to the study team), would you be willing to serve as the Cancer in the Older Adult co-chair for this study? ◻ Yes. ◻ No, please provide a recommendation for a Cancer in the Older Adult Co-Chair: ◻ No, Older Adult Committee member not necessary. Additional comments for study team consideration: a Trials should include an analysis of relevant endpoints in those aged 65 years and older that is powered to identify the differences between those endpoints. b If N/A or not necessary are checked, an explanation should be given to explain why. Open in new tab Table 3. The Alliance’s Cancer in Older Adult Committee Check List for Study Concept Review CANCER IN OLDER ADULT COMMITTEE CHECKLIST FOR STUDY CONCEPT REVIEW Reviewed by Date: 1. Is this concept applicable to older patients with cancer (≥65 years of age)? ◻ Yes, proceed to next question. ◻ No, your review is complete and the rest of the form does not need to be completed. Additional comments for consideration: 2. Is there an upper age limit on this concept (and/or is Inclusion Across the Lifespan addressed in this concept)? ◻ No. ◻ Yes, the upper age limit is appropriate for this concept and rationale for the age cut-off is provided. ◻ Yes, the upper age limit is appropriate for this concept; however, a rationale for the age cut-off is not provided and needs to be included. ◻ Yes, the upper age limit is NOT appropriate for this concept. Please explain your concerns and provide recommendations: Note: If possible/relevant, please provide a reference(s) to support your recommendation: 3. Are inclusion criteria appropriate and as broad as possible with respect to enrolling older patients with cancer? ◻ Yes, no changes recommended. ◻ No, explain your concerns and provide recommendation: 4. Are endpoints relevant to older adults with cancer (such as the impact of treatment on function) already included in this concept? ◻ Yes, skip the next question. ◻ No, but this is not relevant to this concept. ◻ No, please consider the following endpoints relevant to older adults with cancer (comments below). Comments and recommendations: 5. Are there measures to ensure that sufficient numbers of older patients are enrolled to the study (ie, proportions of older patients enrolled reflect the proportions in the population?)a ◻ Yes, not applicable, this study is dedicated to older patients with cancer. ◻ Yes, the study design specifies the number of older patients with cancer that will need to be enrolled. ◻ Yes, other, explain. ◻ No, not applicable to this study. ◻ No, I would recommend adequate numbers of older patients be enrolled to this study. Please provide details for this recommendation: 6. Is the geriatric assessment included? ◻ Yes. ◻ No, I do not recommend that the geriatric assessment be included. ◻ No, I recommend that the geriatric assessment be included. Please provide details for this recommendation (eg, rationale for including, correlative endpoint, time points recommended): 7. Independent of the geriatric assessment, are there other core measures included for this study regarding comorbidity, or baseline blood work that should be collected? ◻ Yes, what are they? ◻ No, I recommend that the following core measures be considered: 8. Has the study team already engaged someone from the Cancer in the Older Adult Committee in designing this study? ◻ Yes (Name __________________________) ◻ No ◻ N/A I don’t think this is necessary.b 9. If this concept is approved for protocol development (and it is appropriate to add a committee member to the study team), would you be willing to serve as the Cancer in the Older Adult co-chair for this study? ◻ Yes. ◻ No, please provide a recommendation for a Cancer in the Older Adult Co-Chair: ◻ No, Older Adult Committee member not necessary. Additional comments for study team consideration: CANCER IN OLDER ADULT COMMITTEE CHECKLIST FOR STUDY CONCEPT REVIEW Reviewed by Date: 1. Is this concept applicable to older patients with cancer (≥65 years of age)? ◻ Yes, proceed to next question. ◻ No, your review is complete and the rest of the form does not need to be completed. Additional comments for consideration: 2. Is there an upper age limit on this concept (and/or is Inclusion Across the Lifespan addressed in this concept)? ◻ No. ◻ Yes, the upper age limit is appropriate for this concept and rationale for the age cut-off is provided. ◻ Yes, the upper age limit is appropriate for this concept; however, a rationale for the age cut-off is not provided and needs to be included. ◻ Yes, the upper age limit is NOT appropriate for this concept. Please explain your concerns and provide recommendations: Note: If possible/relevant, please provide a reference(s) to support your recommendation: 3. Are inclusion criteria appropriate and as broad as possible with respect to enrolling older patients with cancer? ◻ Yes, no changes recommended. ◻ No, explain your concerns and provide recommendation: 4. Are endpoints relevant to older adults with cancer (such as the impact of treatment on function) already included in this concept? ◻ Yes, skip the next question. ◻ No, but this is not relevant to this concept. ◻ No, please consider the following endpoints relevant to older adults with cancer (comments below). Comments and recommendations: 5. Are there measures to ensure that sufficient numbers of older patients are enrolled to the study (ie, proportions of older patients enrolled reflect the proportions in the population?)a ◻ Yes, not applicable, this study is dedicated to older patients with cancer. ◻ Yes, the study design specifies the number of older patients with cancer that will need to be enrolled. ◻ Yes, other, explain. ◻ No, not applicable to this study. ◻ No, I would recommend adequate numbers of older patients be enrolled to this study. Please provide details for this recommendation: 6. Is the geriatric assessment included? ◻ Yes. ◻ No, I do not recommend that the geriatric assessment be included. ◻ No, I recommend that the geriatric assessment be included. Please provide details for this recommendation (eg, rationale for including, correlative endpoint, time points recommended): 7. Independent of the geriatric assessment, are there other core measures included for this study regarding comorbidity, or baseline blood work that should be collected? ◻ Yes, what are they? ◻ No, I recommend that the following core measures be considered: 8. Has the study team already engaged someone from the Cancer in the Older Adult Committee in designing this study? ◻ Yes (Name __________________________) ◻ No ◻ N/A I don’t think this is necessary.b 9. If this concept is approved for protocol development (and it is appropriate to add a committee member to the study team), would you be willing to serve as the Cancer in the Older Adult co-chair for this study? ◻ Yes. ◻ No, please provide a recommendation for a Cancer in the Older Adult Co-Chair: ◻ No, Older Adult Committee member not necessary. Additional comments for study team consideration: a Trials should include an analysis of relevant endpoints in those aged 65 years and older that is powered to identify the differences between those endpoints. b If N/A or not necessary are checked, an explanation should be given to explain why. Open in new tab Standard language for site training and caregiver materials is also recommended. A relevant model is the Common Terminology Criteria for Adverse Events and Patient Reported Outcomes protocol template (https://healthcaredelivery.cancer.gov/pro-ctcae/measurement.html). Third, because it is well recognized that older adults are underrepresented in cancer clinical trials, specific plans to recruit this population, with standard operating procedures, should be developed and required for trials specific to older adults and trials for which older adults are eligible. This resource specific to older cancer patients will provide investigators with expert-developed resources to improve quality and reduce duplicative efforts around research and enrollment of older adults. Lastly, we recommend that there be centralized support from experts in geriatric ocology that can be leveraged locally. One potential resource is the Cancer in Aging Research Group (CARG; mycarg.org). CARG is the largest organization for cancer and aging scholars in North America and is support by an National Institute on Aging infrastructure grant (5R33AG059206) to make resources available, allowing a mechanism to submit inquiries, find expertise, receive analytic input, and obtain aging-specific expert feedback. Other organizations, such as the International Society of Geriatric Oncology, American Society for Clinical Oncology, the American Geriatrics Society, and the Association of Community Cancer Centers, are also available to provide input. Harmonizing resources across such groups would be valuable. The availability of these centralized resources for concept and protocol development and of consultants with expertise in geriatrics and geriatric oncology would provide investigators with the means to optimally enroll and treat older patients in cancer clinical trials. Still, there are several unanswered questions regarding these resources. We realize that as systems continue to change, ongoing evaluation and improvement will be necessary to make sure that key resources are readily available and harmonized across groups. There is also the concern regarding the storage and updating of these resources to maintain wide availability. Because cancer in older adults is a global health issue, not a local or even national one, the institution that is responsible for maintaining the resources should be one that not only makes them widely available but ensures they are multilingual and culturally sensitive as well. Furthermore, regular vetting of the existing resources and the uptake of new ones must be conducted to ensure accuracy, quality, and appropriate use. Such monitoring would provide feedback that will lead to resource updates, based on utilization and what modifications are deemed necessary to make accrual successful in various settings. Most importantly, we recognize the importance of access and equitable dissemination. Champions will be needed to spread the word about the availability of these resources and to encourage use. Then, a system will need to be developed to make adjustments to monitor implementation and facilitate use. Such coordination requires underlying infrastructure, including expertise, transparent processes, and high-quality vetting processes. Recommendation 2: Training for Clinical Research Staff Current guideline recommendations are that geriatric assessment (GA) be standard of care in all older patients with cancer starting on systemic therapy (18-20); the uptake of this practice is low. In a recent international survey of oncology providers, only 20% reported routinely employing a GA in the management of their older patients considering chemotherapy (21). Furthermore, there is no consensus on the appropriate way to approach this assessment, whether by screening for problems and referring only some patients for comprehensive GA (CGA) or by having CGA, or certain portions of the CGA, done in all older adults with cancer. In addition, there has been limited formal training for performing GA across all clinical and research sites, which results in variability in instrument selection and scoring (missing data). One way to address the low uptake of GA inclusion in trials is to provide better training for staff for obtaining the GA. Although this does not immediately solve the concern about use of the GA results, it may provide greater consistency in the data collection. An example of the effective use of GA training comes from the Alliance for Cancer Clinical Trials. The Cancer in Older Adults Committee for the Alliance developed and pilot-tested a cancer-specific GA for use in its clinical trials (22,23). In partnership with policies to require its use, along with training in the use of the GA, broader uptake has occurred. The CARG also compiled data from using an abbreviated CGA in older patients with cancer and developed a tool by which chemotherapy toxicity is accurately predicted (24-26). This tool has now been incorporated into intervention trials and is available for public use through the CARG website. Another example of use of GA in research comes from a cluster-randomized clinical trial from the NCORP who studied the use of GA in oncology visits and found that communication about aging-related concerns was improved (27). Further development of training materials, whether video or printed, can maximize the widespread use of the GA in more locations without needing additional staff. We, therefore, recommend that GA training be delivered to research staff online and that the completion of the training be tracked. One possible format would be through the NCI learning management system. Standardization of GA training will also help identify processes that can be improved and streamlined. The target audience for this training will include, but not be limited to, principal investigators, clinical research professionals, and others administering the GA. Availability of centralized training would also allow consistent training to reduce duplication of work for sites and groups and improve data collection and quality. Key GA training needs should be analyzed, identified, and tracked, which will require an ongoing evaluation process. Recommendation 3: Development of CDEs The plethora of different GA tools and the lack of consensus on their use creates challenge in designing trials. In addition, there is confusion about whether the GA should be performed as a pretreatment evaluation to gather baseline data or as an outcome measure. It is important that data elements, or variables, whether for baseline assessment or for outcome measurement, be carefully defined and consistently collected in clinical research. These elements, including GA specific items, are important for defining trial eligibility, developing intervention, guiding on-trial monitoring and data collection, and reporting study outcomes. The data elements uniquely important in older patients with cancer include geriatric syndromes, as defined by a GA, and other issues especially important to older patients, such as vision and hearing deficits. As a starting point, we suggest that the GA be used to structure CDEs for cancer clinical trials for older adults. The domains of the GA, including functional status, comorbidity, cognitive function, nutrition, psychological state and social support, and polypharmacy, are well established (28). Assessment of each has been defined by multiple and various measures, and only some of these have been specifically studied in populations of older patients with cancer. There are multiple forms of GA, including mailed, self-administered, electronic, collected from administrative databases, clinician assessed, and others. Some have been validated in patients with cancer and some in only certain types of cancers. As a result, data reporting is highly variable. Similar or identical GA items are often being collected in separate study databases. There is inconsistency in data descriptors, which makes it extremely difficult to aggregate and manage aging-related data across studies. We, therefore, recommend standardization of GA data nomenclature for the reporting of NCI trials. One possibility is for work to be done with NCI to add CDEs for key GA items to the NCI CDE browser for use in future NCTN and NCORP trial case report forms. For these new items, we will need to work with statisticians and data managers to develop electronic case report forms for key GA tools that can be adapted by individual groups and research bases. The advantages of this approach will be the reduction in duplication of effort and improved efficiency. It will also encourage consistent centralized data collection to facilitate aggregate analyses. There are remaining questions about the feasibility of collecting GA data in trials and whether it is feasible to have clinical research professionals input the data into the Medidata Rave Electronic Data Capture (RAVE) system or other data capturing systems. Ongoing evaluation of the process will help define other ways to facilitate collection and analysis of GA data in NCTN and NCORP trials. Recommendation 4: Evaluation of Enrollment Interventions A likely reason for the lack of improvement in enrollment of older adults in cancer clinical trials is failure to systematically study interventions to improve accrual. We realize that it is difficult to implement change in systems, especially across all NCTN and NCORP trials. We therefore recommend a strategic approach that first assesses the current landscape, evaluates what has led to successful accrual of older adults to clinical trials, and develops targeted interventions in disease areas that are struggling to enroll older adults. Assessment of our current status is available in the literature (13). There are some examples in the literature of studies that were successful in accruing older adults, such as those that were specific to older adults (29) and those that include cancer types and treatments pertinent to older adults. Trials for older adults can be pragmatic and performed in the community. Dr Mohile and colleagues demonstrated what is possible with their cluster randomized intervention trial in adults aged older than 70 years with at least 1 deficit on a GA across 31 community oncology clinics in the NCORP (30). This large trial of more than 700 patients showed that use of a GA-guided intervention reduced chemotherapy-related grade 3-5 toxicity in vulnerable older adults with advanced cancer. The methods used to recruit and enroll such patients (and their families) can serve as a model for others. Older adult-specific trials have also been successful in incorporating relevant assessments, including the GA. In a chronic lymphocytic leukemia phase III treatment trial testing first-line ibrutinib or ibrutinib with rituximab vs chemo-immunotherapy in patients aged 65 years or older, 74% of the 547 patients consented to have the GA done, of which 95% completed the baseline GA (31). In another trial, a phase II study of first-line sorafenib and chemotherapy in patients aged 60 years or older with acute myeloid leukemia, 80% of patients consented to the GA and 93% of these patients completed the baseline GA (32). Again, this demonstrates that trials designed for older adults can successfully incorporate relevant aging-related endpoints. Another opportunity to use infrastructure to make trials more relevant to older patients with cancer is to design trials to test enrollment in GA-guided intervention studies. An example of such intervention-based trial designs is differential dosing studies in which lower doses of cancer therapies are tested against standard doses. There have been several examples of successfully conducted studies in older adults with colon, ovarian, and gastric cancer where investigators tested the efficacy and safety of reduced intensity treatment (33-35). Another approach is to allow trial designs that are specifically adapted to older adults. Examples of such adapted clinical trial advances include studies where therapies are adjusted (intensified or de-intensified) according to frailty metrics (36). Although the results from these studies differ across diseases and populations, this type of study design represents a critical opportunity for investigating the optimal delivery of cancer treatment in older adults. Such interventional trial designs require changes in policies and procedures, which are crucial aspects of infrastructure. Moving beyond GA, we recommend iterative clinical trial design based on lessons learned from other investigators collated in the proposed centralized resource. Investigators, groups, and sites who have demonstrated success in accrual of older adults should be queried about their methods and insights into the problem. Then, we can utilize these lessons learned to inform design and recruitment and/or retention of other studies, thus leading to specific interventions to improve accrual in disease areas that are struggling to enroll older adults. By using a targeted approach and learning from what works and what does not, we can develop new approaches. This will help us pilot new ideas, show feasibility, and enhance future broad implementation. To evaluate the success of this approach, we will need to define successful, low, and high enrollment of older adults to NCTN and NCORP trials. Priorities will also need to be set, such that the areas of greatest need are targeted. Discussion In summary, a multipronged approach toward improving infrastructure, which includes people, processes, and policies, is warranted to potentially improve recruitment, enrollment, and accrual of older patients into cancer clinical trials. Addressing infrastructural barriers is a critical priority to remove key barriers to clinical trial accrual. This includes 1) centralizing existing resources and expertise; 2) training clinical research staff in use of the GA; 3) developing CDEs to increase knowledge; and 4) evaluating which interventions are most effective. Such infrastructure changes, in coordination, could function as a recruitment core resource on a national level to important scientific questions relevant for older adults. These actionable changes can be made in the near future and, in combination with other approaches described elsewhere in this issue of the journal, can make meaningful differences toward improving enrollment of older adults. We hope that these initial resources help lay the foundation for additional changes. Recognizing that this is a start to a much larger program of change, these meaningful changes to existing infrastructure set the stage for a broader, coordinated approach to the accrual of older adults. As we think about the future, we should consider how to restructure our approach to interventional clinical research, to embed aging concerns as a focus, and to ensure that older adults, in whom cancer is most common, are not left behind as the therapeutic options expand. We need to plant the seeds of a more inclusive clinical trial system that considers the needs of older adults and is inclusive of all vulnerable patients. Rather than ask patients and families to adapt to our system, we should be designing a recruitment system to best accommodate the needs of our older adult patients. Funding The workshop was coordinated by the National Cancer Institute Division of Cancer Prevention in collaboration with the Division of Cancer Treatment and Diagnosis. Writing of this manuscript was not funded. National Cancer Institute staff provided minor edits to the final manuscript. Notes Disclosures: Authors have nothing directly related to the manuscript to disclose. Author contributions: Drs Kimmick and Sedrak composed the summary of this part of the symposium; Dr Dale helped organize the symposium, oversee the agenda, and summarize the findings; all authors reviewed and approved the manuscript. Acknowledgements: We acknowledge the leadership and support from the Cancer and Aging Research Group for their role in supporting this work. Disclaimers: None. Prior presentations: This manuscript is the summary from the Infrastructure Working Group from “Engaging Older Adults in the NCI Clinical Trails Network: Challenges and Opportunities,” a workshop held April 26-27, 2021. 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JNCI Monographs – Oxford University Press

Published: Dec 15, 2022

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