Part 1. Overview Information

Key Dates

Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions.

Applications that do not comply with these instructions may be delayed or not accepted for review.

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

This FOA invites R61/R33 applications to develop interventions for physician compliance with recommended prevention guidelines for older adults from the CDC and the USPTF. Specifically, applicants will develop electronic health record (EHR)-based interventions to improve the quality of care and health outcomes and reduce health disparities. Although applicants can collaborate with insurers and healthcare facilities, incorporating payment incentives is not the focus of this FOA, and this FOA will not cover monetary incentive payments to physicians for adhering to CDC and USPTF recommendations and guidelines. Applicants can build tools into EHRs, as well as to leverage systems that already have these features, demonstrating how interventions can improve clinician and patient behavior and patient outcomes.

Background/Need

In recent years we have seen dramatic increases in the adoption of EHRs, expanding the amount of clinical data available to inform preventive interventions to improve the health of older adults. Simultaneously, rapid progress has been made in clinical analytics techniques for analyzing these large quantities of data to glean new insights to inform interventions.

This FOA encourages researchers to use insights from EHRs and other data sources (e.g., Centers for Medicare and Medicaid Services (CMS) claims records) to create personalized interventions for both physicians and patients to improve the uptake and impact of preventive care recommendations from the USPTF (e.g., regular cancer screenings) and immunization recommendations from the CDC (e.g., Zoster vaccine for shingles), which could significantly improve the well-being of older adults. This FOA requires data analytics and development of interventions which will: (1) identify high-risk patients, (2) personalize preventive interventions for patients and providers, and (3) improve uptake of preventive clinical guidelines. This FOA requires all applicants to create interventions for both providers and patients to address health disparities (e.g., colorectal cancer is the second leading cause of cancer death, yet the take-up of screening is low among Hispanics compared to other racial and ethnic groups).

Partnerships and Access to Electronic Health Records

Partnerships with healthcare delivery organizations will be critical in implementing this FOA. It is anticipated that the interventions will generally be performed with electronically supported, integrated healthcare delivery organizations looking to establish efficiencies. The partnership must facilitate access to all EHR data sources relevant to the project (modifying the system when necessary). Further, we encourage collaborations with retail EHR vendors (EPIC, eClinical, MedSeek, etc.) to scale the adoption of successful interventions to solo and small-group practices.

Scope of the FOA

Applications submitted to this FOA should exploit data from EHRs or other administrative data (e.g., CMS claims data) coupled with interventions targeting compliance with recommended treatment guidelines. The Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) should form a multidisciplinary, collaborative research team with expertise in medicine, behavioral and social sciences (e.g., psychology, economics, etc.), and bioinformatics/data science to carry out the research objectives. The FOA encourages participation of both large and small health delivery networks, such as primary care physicians, geriatricians, or Health Management Organizations (HMOs), in order to implement interventions.

NIA seeks applications that will integrate simple, low-cost interventions in EHRs to improve physician and patient adherence to CDC recommendations and USPTF treatment guidelines. NIA particularly encourages applications which address the following:

• USPSTF Grade A and B Recommendations focusing on adults above age 50
• Recommendations by the CDC Advisory Committee on Immunization Practices for adults above age 50

These interventions must be simple, inexpensive, and powerful enough to move directly from Stage I (creation, adaptation, and piloting of an intervention) to Stage IV pragmatic trials testing the effectiveness of the intervention. (Please see NIH Stage Model.) More complex interventions that require additional Stage I work, such as the development and testing of physician/provider training materials or other materials to ensure fidelity, may be included only if such Stage I testing may be conducted within the R61 phase and if a compelling case can be made that traditional Stage III testing (highly-controlled, high-internal-validity, community-based) is not needed before proceeding to Stage IV (high-external-validity pragmatic trials).

The R61 Phase (Planning Phase, Including Stage I Research)

During the R61 pilot phase, using EHR and data analytics tools, researchers will establish the feasibility of identifying groups of patients not getting preventive care. They will conduct Stage I research to create tailored interventions to integrate preventive guidelines within the EHR. If successful, interventions can transition to an R33 phase for implementation of Stage IV pragmatic trials. The specific activities and milestones appropriate for the R61 phase will depend on the type of intervention and its stage of development. The applicant must include the following activities and milestones for the R61 phase:

• Utilize analytical tools, including machine learning approaches, to establish the feasibility of identifying groups of patients not getting preventive care, including identification of high risk and vulnerable patients and personalization of interventions for patients and providers.
• Using information gleaned from the EHR, conduct Stage I research to create interventions to overcome barriers affecting each group. Researchers are required to design interventions which will address not only the supply side (e.g., healthcare providers ordering preventive services), but also actual uptake of preventive services by patients.
• Establish a partnership with healthcare providers (e.g., primary care physicians, geriatricians, specialists, HMOs, etc.) and document commitment of the organizations to the project.
• Operationalize definitions and objective measures of the intervention.
• Propose a hypothesized mechanism to achieve the FOA objective.
• Provide preliminary evidence that the mechanism of action can be manipulated reliably and validly through the EHR-supported process.
• Assess and justify adequacy and finalize clinically relevant outcome measures.
• Pilot testing intervention(s) and produce preliminary data for R33 administrative review showing feasibility, including pragmatic trial protocol.

The R33 Phase (Implementation Phase, Stage IV Pragmatic Trial)

During the R33 phase, PD(s)/PI(s) will implement the intervention in a clinical setting, including the following general activities:

• Use results from the R61 phase to further refine, standardize, and test the feasibility, safety, and acceptability of the intervention. This includes testing the association between the intervention and clinical outcomes.
• Based on findings from the R61 phase and guidance from NIH staff, refine estimates for sample size, number of sites, site-to-site heterogeneity, and the implementation timetable. Additionally, in order to ensure all studies supported by the R33 phase are adequately powered, it is recommended that the PD(s)/PI(s) provide power calculations
• Use R61 findings to update the R33 plan for site implementation, including recruitment of site staff, method of participant identification and randomization (if applicable), participant recruitment, and acquisition of data.
• Address all ethical issues related to human subject safety oversight for the pragmatic trials which arose during the R61 phase, including the development of informed consent or opt-out consent documents (if applicable).
• Finalize site of IRB review. Applicants must propose a single IRB approach for trial oversight to facilitate appropriate and timely study implementation.
• Replicate findings in another site. Applicants are required to identify additional implementation sites for replication purposes prior to beginning the R33 phase.

Milestones and R61/R33 Transition

The application must propose a well-defined set of milestones (see required milestones in the R61 phase section above) for the planning phase (R61) and annual milestones for the implementation phase (R33). Specifically, the transition from the R61 to the R33 phase of the award will be administratively reviewed for successful completion of the go/no-go criteria that must be clearly specified in the R61 phase. Applicants can establish go/no-go criteria as they deem fit for their application, but they must include the following:

(1) Demonstration of the feasibility of applying data analysis to identify groups of patients not getting preventive care and tailoring interventions to overcome barriers

(2) Established partnerships with healthcare providers documenting the commitment of the organization to the project

(3) Ability to obtain access to EHRs and modify and implement pilot interventions

(4) Operationalized definitions and objective measures of the intervention (i.e., the hypothesized mechanism of action)

(5) Provision of preliminary evidence that the mechanism of action can be manipulated reliably and validly through the EHR process

(6) Assessment and justification of adequacy and finalization of clinically-relevant outcome measures

(7) Results of the pilot test intervention(s) and preliminary data for R33 administrative review showing feasibility of the intervention and completion of pragmatic trial protocol

At the completion of the R61 planning phase, the applicant will be required to submit a detailed transition request for the R33 implementation phase.

Prospective applicants should note that funding of a grant application for the R61 phase does not guarantee support of the R33 phase. Transition to the R33 phase of the project will occur only if an administrative review process recommends that the R61 planning activities have been successful, the implementation phase of the project can proceed with confidence of success, and funds are available.

Research Resources and Data Sharing

Consistent with achieving the goals of the program, researchers are expected to share all study data and resources generated from the grant in a timely manner with appropriate privacy and confidentiality protections to facilitate rigor and reproducibility. Resources may include, but are not limited to, software, tools, code sets for extraction, definition of data from EHR, clinical systems and other healthcare data systems, implementation of new workflows for research studies, data analysis programs, analytical codes (e.g., SAS ot STATA files), and tools for incorporating patient input.

Responsiveness Criteria

Applications on these topics will not be considered responsive and will not be reviewed:

• Trials not addressing USPTF Grade A and B Recommendations for adults above age 50 or recommendations by the CDC Advisory Committee on Immunization Practices for adults above age 50
• Trials without a control group identified (i.e. open trials)
• Trials which require complex or expensive implementation or monitoring during R33 phase (i.e. trials not classified under Stage IV pragmatic trials)
• Trials which do not leverage opportunities through EHRs
• Trials not addressing health disparities
• Trials not personalizing preventive interventions for patients and providers

ODP Priority Statement

The Office of Disease Prevention (ODP) is interested in co-funding research designed to detect and prevent progression of an asymptomatic or early-stage health condition and identify risk factors for the progression or recurrence of health conditions. ODP is also interested in research that promotes the uptake of evidence-based interventions with a specific focus on screening for conditions that include, but are not limited to, those deemed high-priority evidence gaps by the US Preventive Services Task Force. Further, ODP is interested in investigations that identify approaches for addressing the need to coordinate screenings for several chronic diseases that might be recommended in the course of a single primary care encounter.

Section II. Award Information

Section III. Eligibility Information

1. Eligible Applicants

Higher Education Institutions

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

• Small Businesses
• For-Profit Organizations (Other than Small Businesses)

Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)
• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations

Applicant organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
  • NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
• eRA Commons - Applicants must have an active DUNS number to register in eRA Commons. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration , but all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

2. Cost Sharing

This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.

3. Additional Information on Eligibility

Number of Applications

The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101)

Section IV. Application and Submission Information

1. Requesting an Application Package

The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

Letter of Intent

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:

• Descriptive title of proposed activity
• Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
• Names of other key personnel
• Participating institution(s)
• Number and title of this funding opportunity

The letter of intent should be sent to:

Partha Bhattacharyya, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-496-3136
Email: bhattacharyyap@mail.nih.gov

All instructions in the SF424 (R&R) Application Guide must be followed.

Applicants should budget for travel to a one-day annual investigators meeting to be held in the Washington, D.C. area.

Specific Aims: Separate specific aims should be presented for both the R61 and R33 phases on one page.

Research Strategy: The research strategy should contain separate sections that describe both the R61 and R33 phases. Separate research design and methods could be presented as needed for the R61 and R33 phases. It is not necessary to repeat information or details in the R33 section that are described in the R61 section.

Preliminary data are not required for an R61/R33 application. However, any preliminary data that will support or justify the proposed hypothesis, rationale, or development plan may be included.

PD(s)/PI(s) should propose to follow best practices for the conduct of their randomized trial and clearly state how randomization will be performed. For example, if randomization is performed at the hospital level, the applicant should describe how many effective observations will there be after accounting for intra-cluster correlation. If the randomization is at a lower level than the hospital, the PD(s)/PI(s) should address potential threats to validity due to contamination across treatment groups. PD(s)/PI(s) should clearly present power calculations that reflect a range of effect sizes of clinical significance. Specifically, it is recommended that PD(s)/PI(s) provide beta ranges to assess the sample size and effect size across multiple sites.

Applicants should provide a description of how the study designs, methods, and assessments are complementary, such that outcomes from the planning phase will enhance the interpretation of outcomes at the implementation stage. For example, in the planning phase the PD(s)/PI(s) may propose only one intervention (e.g., peer comparison) in a single site and implement it in EHR to show the feasibility of physician participation. In the implementation phase the PD(s)/PI(s) may propose multiple interventions which can improve physicians' adherence to guidelines (e.g. default settings in EHRs, peer comparison within and outside the health system, texting patients to remind them about preventive care, etc.) across multiple sites.

Since the intent of this announcement is to leverage findings from the planning phase to the implementation phase and increase the potential for translation research, the PD(s)/PI(s) are encouraged to collaborate with EHR vendors to maximize the possibility of translation.

Milestones and R61/R33 Transition

The application must include milestones the researchers expect to achieve by the end of the R61 phase, as well as milestones for the R33 phase. Milestones should be specific, quantifiable, and scientifically justified; they should not be simply a restatement of the specific aims for the R61 phase. It is recommended that PD(s)/PI(s) include a section labeled "milestones" describing milestones to be achieved during the R61 phase to qualify for the transition to the R33.

It is understood that the proposed milestones for the R33 phase may be revised based on activities during the R61 phase. In the event of an award, the PD(s)/PI(s) and NIH staff will negotiate a list of milestones for each year of support.

The following modifications also apply:

• All applications, regardless of the amount of direct costs requested for any one year, must address a Data Sharing Plan.
  • Investigators should indicate the repository/consortium/enclave where they will place data or have a clear plan and the capacity to share data from their own site(s). Investigators should describe any transformations (application of algorithms, tools) that will be applied to the data in preparing them to be shared.
  • Investigators should describe and justify the data release timetable. Generally, the data from a publication should be made available by the online publication date unless NIH policy specifies an earlier date. Investigators should justify exceptions to that timing.
  • Investigators should identify any restrictions on sharing (beyond temporal restrictions) and justify them. Restrictions might include, for example, no commercial use of the data, limiting data access to qualified users, or forbidding the sharing of personal or private information. Investigators may also set different levels of access, for example, for expert users and novice users.
  • For studies involving human participants, investigators should describe how they will de-identify the data, whether that procedure is one following HIPAA, IRB, or other institutional guidance, and generally how they will secure the personal and private information of the participants.
  • Investigators should describe how they will curate the data and what documentation they will provide ( metadata ), in what format, and whether any data will be held back, and if they will work with an identified repository/consortium/enclave to prepare the data and documentation to allow easy access to qualified users.
  • In order to encourage rigor and reproducibility, all applications where the development of statistical codes (e.g., STATA, SAS, R, etc.) or other resources (e.g., instruments, algorithms for machine learning, codes associated with prompts for EHRs) are expected should describe a specific plan for sharing and distributing unique research resources generated using NIH funding or state why such sharing is restricted or not possible.

If you answered Yes to the question Are Human Subjects Involved? on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the SF424 (R&R) Application Guide must be followed.

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).All instructions in the SF424 (R&R) Application Guide must be followed.

3. Unique Entity Identifier and System for Award Management (SAM)

See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

4. Submission Dates and Times

Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday , the application deadline is automatically extended to the next business day.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement .

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

7. Other Submission Requirements and Information

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit How to Apply Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

In order to expedite review, applicants are requested to notify the NIA Referral Office by email at Ramesh.Vemuri@nih.gov when the application has been submitted. Please include the FOA number and title, PD/PI name, and title of the application.

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process. Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

A proposed Clinical Trial application may include study design, methods, and intervention that are not by themselves innovative but address important questions or unmet needs. Additionally, the results of the clinical trial may indicate that further clinical development of the intervention is unwarranted or lead to new avenues of scientific investigation.

This particular announcement is a R61/R33 phased innovation grant which will support interventions through EHRs to deliver appropriate preventive care without overruling physicians autonomy. An R61/R33 grant application need not have preliminary data, extensive background material, or preliminary information; however, these may be included if available. Appropriate justification for the proposed work can be provided through literature citations; data from other sources; or, when available, investigator-generated data. Reviewers will focus their evaluation on the conceptual framework, the level of innovation for implementing preventive interventions in EHRs, and the potential to significantly advance our knowledge or understanding. Since implementation of preventive care through EHRs is an emerging research area, investigators may not have experience working together as a team, as expertise may be necessary from multiple disciplines (e.g. medicine, bio-statistics, economics, psychology, etc.). Reviewers will assign a single impact score for the entire application, which includes both the R61 and R33 phases.

Significance

Does the project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Are the scientific rationale and need for a clinical trial to test the proposed hypothesis or intervention well supported by preliminary data, clinical and/or preclinical studies, or information in the literature or knowledge of biological mechanisms? For trials focusing on clinical or public health endpoints, is this clinical trial necessary for testing the safety, efficacy or effectiveness of an intervention that could lead to a change in clinical practice, community behaviors or health care policy? For trials focusing on mechanistic, behavioral, physiological, biochemical, or other biomedical endpoints, is this trial needed to advance scientific understanding?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

With regard to the proposed leadership for the project, do the PD/PI(s) and key personnel have the expertise, experience, and ability to organize, manage and implement the proposed clinical trial and meet milestones and timelines? Do they have appropriate expertise in study coordination, data management and statistics? For a multicenter trial, is the organizational structure appropriate and does the application identify a core of potential center investigators and staffing for a coordinating center?

Innovation

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

Does the design/research plan include innovative elements, as appropriate, that enhance its sensitivity, potential for information or potential to advance scientific knowledge or clinical practice?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed project ? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

Is there a unifying and testable hypothesis that transcends both the R61 and R33 phases? Does the application provide clear milestones for the R61 phase and related scientific goals for the R33 phase? Are those milestones conducive to accomplishing the study aims? Are the goals of the R33 phase based, in part, on findings collected during the R61 phase? Did the PD(s)/PI(s) establish an appropriate partnership with one or more healthcare provider(s) (e.g., primary care physicians, specialists, HMOs, etc.) and document the commitment of the organization(s) to the project? Will the PD(s)/PI(s) be able to access an EHR system to modify and implement pilot interventions with providers and patients (e.g. is there an appropriate letter of support)? Did the PD(s)/PI(s) provide adequate power calculations and adequate justification?

Did the PD(s)/PI(s) operationalize definitions and objective measures of the intervention (i.e., did the PD(s)/PI(s) cite evidence base to support that the hypothesized mechanism of action can be manipulated and implemented in EHRs)? Did the applicant assess and justify adequacy and finalize clinically-relevant outcome measures? Will the R61 phase produce preliminary data for R33 administrative review showing feasibility?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?

Does the application adequately address the following, if applicable?

Study Design

Is the study design justified and appropriate to address primary and secondary outcome variable(s)/endpoints that will be clear, informative and relevant to the hypothesis being tested? Is the scientific rationale/premise of the study based on previously well-designed preclinical and/or clinical research? Given the methods used to assign participants and deliver interventions, is the study design adequately powered to answer the research question(s), test the proposed hypothesis/hypotheses, and provide interpretable results? Is the trial appropriately designed to conduct the research efficiently? Are the study populations (size, gender, age, demographic group), proposed intervention arms/dose, and duration of the trial, appropriate and well justified?

Are potential ethical issues adequately addressed? Is the process for obtaining informed consent or assent appropriate? Is the eligible population available? Are the plans for recruitment outreach, enrollment, retention, handling dropouts, missed visits, and losses to follow-up appropriate to ensure robust data collection? Are the planned recruitment timelines feasible and is the plan to monitor accrual adequate? Has the need for randomization (or not), masking (if appropriate), controls, and inclusion/exclusion criteria been addressed? Are differences addressed, if applicable, in the intervention effect due to sex/gender and race/ethnicity?

Are the plans to standardize, assure quality of, and monitor adherence to, the trial protocol and data collection or distribution guidelines appropriate? Is there a plan to obtain required study agent(s)? Does the application propose to use existing available resources, as applicable?

Data Management and Statistical Analysis

Are planned analyses and statistical approach appropriate for the proposed study design and methods used to assign participants and deliver interventions? Are the procedures for data management and quality control of data adequate at clinical site(s) or at center laboratories, as applicable? Have the methods for standardization of procedures for data management to assess the effect of the intervention and quality control been addressed? Is there a plan to complete data analysis within the proposed period of the award?

Environment

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

If proposed, are the administrative, data coordinating, enrollment and laboratory/testing centers, appropriate for the trial proposed?

Does the application adequately address the capability and ability to conduct the trial at the proposed site(s) or centers? Are the plans to add or drop enrollment centers, as needed, appropriate?

If international site(s) is/are proposed, does the application adequately address the complexity of executing the clinical trial?

If multi-sites/centers, is there evidence of the ability of the individual site or center to: (1) enroll the proposed numbers; (2) adhere to the protocol; (3) collect and transmit data in an accurate and timely fashion; and (4) operate within the proposed organizational structure?

Study Timeline

Is the study timeline described in detail, taking into account start-up activities, the anticipated rate of enrollment, and planned follow-up assessment? Is the projected timeline feasible and well justified? Does the project incorporate efficiencies and utilize existing resources (e.g., CTSAs, practice-based research networks, electronic medical records, administrative database, or patient registries) to increase the efficiency of participant enrollment and data collection, as appropriate?

Are potential challenges and corresponding solutions discussed (e.g., strategies that can be implemented in the event of enrollment shortfalls)?

Protections for Human Subjects

For research that involves human subjects but does not involve one of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

Inclusion of Women, Minorities, and Individuals Across the Lifespan

When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of individuals of all ages (including children and older adults) to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Biohazards

Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

Resubmissions

Not Applicable

Renewals

Not Applicable

Revisions

Not Applicable

Applications from Foreign Organizations

Not Applicable

Select Agent Research

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Resource Sharing Plans

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: (1) Data Sharing Plan, and (2) Sharing of Resources such as statistical codes for analyses, machine learning algorithms, codes associated with developments of prompts for EHR, etc.

Authentication of Key Biological and/or Chemical Resources:

For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

Budget and Period of Support

Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s), convened by the National Institute on Aging, in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

• May undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.
• Will receive a written critique.

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.

3. Anticipated Announcement and Award Dates

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

Section VI. Award Administration Information

1. Award Notices

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.

Individual awards are based on the application submitted to, and as approved by, the NIH and are subject to the IC-specific terms and conditions identified in the NoA.

ClinicalTrials.gov: If an award provides for one or more clinical trials. By law (Title VIII, Section 801 of Public Law 110-85), the "responsible party" must register and submit results information for certain applicable clinical trials on the ClinicalTrials.gov Protocol Registration and Results System Information Website (https://register.clinicaltrials.gov). NIH expects registration of all trials whether required under the law or not. For more information, see http://grants.nih.gov/ClinicalTrials_fdaaa/.

Institutional Review Board or Independent Ethics Committee Approval: Grantee institutions must ensure that tall protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the awardee must provide NIH copies of documents related to all major changes in the status of ongoing protocols. Data and Safety Monitoring Requirements: The NIH policy for data and safety monitoring requires oversight and monitoring of all NIH-conducted or -supported human biomedical and behavioral intervention studies (clinical trials) to ensure the safety of participants and the validity and integrity of the data. Further information concerning these requirements is found at http://grants.nih.gov/grants/policy/hs/data_safety.htm and in the application instructions (SF424 (R&R) and PHS 398).

Monitoring Requirements: The NIH policy for data and safety monitoring requires oversight and monitoring of all NIH-conducted or -supported human biomedical and behavioral intervention studies (clinical trials) to ensure the safety of participants and the validity and integrity of the data. Further information concerning these requirements is found at http://grants.nih.gov/grants/policy/hs/data_safety.htm and in the application instructions (SF424 (R&R) and PHS 398).

Investigational New Drug or Investigational Device Exemption Requirements: Consistent with federal regulations, clinical research projects involving the use of investigational therapeutics, vaccines, or other medical interventions (including licensed products and devices for a purpose other than that for which they were licensed) in humans under a research protocol must be performed under a Food and Drug Administration (FDA) investigational new drug (IND) or investigational device exemption (IDE).

2. Administrative and National Policy Requirements

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 Federal awarding agency review of risk posed by applicants. This provision will apply to all NIH grants and cooperative agreements except fellowships.

For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/index.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-individuals/section-1557/index.htmlhttps://www.hhs.gov/civil-rights/for-providers/laws-regulations-guidance/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see https://www.hhs.gov/civil-rights/for-individuals/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

Not Applicable

3. Reporting

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 Award Term and Conditions for Recipient Integrity and Performance Matters.

Section VII. Agency Contacts

Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-945-7573

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: support@grants.gov

Partha Bhattacharyya, Ph.D.
National Insitute on Aging (NIA)
Telephone: 301-496-3136
Email: bhattacharyyap@mail.nih.gov

Dionne C. Godette, Ph.D.
Office of Disease Prevention (ODP)
Telephone: 301-480-1161
Email: dionne.godette@nih.gov

Ramesh Vemuri, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-402-7700
Email: ramesh.vemuri@nih.gov

Nia Pree
National Institute on Aging (NIA)
Telephone: 301-827-6374
Email: nia.pree@mail.nih.gov

Section VIII. Other Information