Part 1. Overview Information

Key Dates

All applications are due by 5:00 PM local time of applicant organization. 

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

No late applications will be accepted for this Notice of Funding Opportunity (NOFO).

It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide, except where instructed to do otherwise (in this NOFO or in a Notice from NIH Guide for Grants and Contracts).

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

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

There are several options available to submit your application through Grants.gov to NIH and Department of Health and Human Services partners. You must use one of these submission options to access the application forms for this opportunity.

1. Use the NIH ASSIST system to prepare, submit and track your application online.
2. Use an institutional system-to-system (S2S) solution to prepare and submit your application to Grants.gov and eRA Commons to track your application. Check with your institutional officials regarding availability.
   
   
3. Use Grants.gov Workspace to prepare and submit your application and eRA Commons to track your application.



Table of Contents
Part 1. Overview Information
Key Dates
Part 2. Full Text of Announcement
Section I. Notice of Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

Part 2. Full Text of Announcement

Section I. Notice of Funding Opportunity Description

The HEAL Coordinated Approaches to Pain Care in Health Care Systems Research Program

The overall goal of the HEAL Coordinated Approaches to Pain Care in Health Care Systems Research Program is to provide evidence and guidance to health care delivery organizations to implement coordinated multidisciplinary care to manage chronic pain. An important objective of the research program is to engage health care systems that currently do not have the infrastructure to provide quality coordinated pain care.  

This Notice of Funding Opportunity (NOFO) solicits UG3/UH3 phased cooperative research applications that propose implementation science methodology to embed existing evidence-based coordinated pain care models into a variety of public and private health care systems (HCS) where this type of care does not exist. Coordinated pain care models of interest to this NOFO are those that are consistent with a biopsychosocial model of pain and provide either integrated pain management centered in and integrated with primary care or provide comprehensive pain management based on referral and in collaboration with primary care. This NOFO intends to support application approaches that include all defined elements of multidisciplinary care that are described below. This NOFO will support studies that build on the evidence base that already exists for coordinated care in pain management. See Integrated and Comprehensive Pain Management Programs: Effectiveness and Harms.

This NOFO intends that the coordinated care model under study be embedded into the health care system (HCS) of the applicant institutions with emphasis  on including populations of patients with greatest need, regardless of the HCS where they receive treatment.

This NOFO will support proposal for models of care that are informed by engagement of stakeholders, including patients, providers, healthcare system executives, policymakers, and payors.

This NOFO intends to support applications that propose one of the following:

• A rigorous implementation trial to embed effective coordinated pain care models into health care systems (HCS) by leveraging resources and infrastructure of the HCS (e.g., primary care referral system, specialty clinics, rehabilitation center, telehealth network).
• A rigorous implementation trial to embed effective coordinated pain care models into HCSs that would benefit from implementation of coordinated pain care but do not frequently participate in research or serve populations that are under-represented in research.

This NOFO will support applicants that propose multidisciplinary coordinated care approaches  and include, at a minimum, an appropriate medication management program, psychological approaches, and physical interventions. Additional interventions such as procedures and complementary interventions may be included. The NOFO will support study teams that include health care providers from multiple disciplines and implementation scientists.

This NOFO solicits UG3/UH3 phased cooperative research applications to conduct efficient, large-scale implementation trials of coordinated care approaches to improve pain related health outcomes in Americans across the lifespan. This NOFO will support applications that target populations who experience health disparities such as higher rates of morbidity and greater barriers to quality pain care than the general population. For the purposes of this funding opportunity, the NIH-designated U.S. health disparity populations definition includes: Blacks/ African Americans, Hispanics/ Latinos, American Indians / Alaska Natives, Asian Americans, Native Hawaiians and other Pacific Islanders, socioeconomically disadvantaged populations, underserved rural populations, and sexual and gender minorities (More information can found at the following link: https://www.nimhd.nih.gov/about/overview/).

Awards made under this NOFO will support a one-year planning phase (UG3) project that may transition to the second phase (UH3) to conduct an implementation or hybrid effectiveness and implementation trial if appropriate scientifically based go/no go criteria (set as study milestones) and feasibility requirements for transition are met. The UG3/UH3 application should be submitted as a single application, following the instructions described in this NOFO.

Governance: The awards funded under this NOFO will be cooperative agreements (see Section VI.2 Cooperative Agreement Terms and Conditions of Award). This program will include individual implementation research projects funded through the NOFO and will be supported by an existing coordinating center:

Coordinating Center (CC):

Trials will be supported by the Coordinating Center (CC) of the HEAL Pragmatic and Implementation Studies to Improve the Management of Pain and Reduce Opioid Prescribing (PRISM) Program, (https://rethinkingclinicaltrials.org/.)  The NIH Pragmatic Trials Collaboratory Resource Coordinating Center will provide technical expertise in all aspects of research and coordination across studies awarded through this NOFO.  This NOFO will support applications that work with the CC to facilitate planning and refinement of proposed studies in partnership with health care delivery systems. The CC is established and is not part of this application.

The Coordinating Center (CC) will: 1) provide leadership for the program and further develop, adapt, and adopt technical and policy guidelines and best practices for the effective conduct of research in partnership with health care systems, including coordinated models of pain care; 2) work collaboratively with each team supported through the HEAL Coordinated Approaches to Pain Care Program by providing technical, design, and coordination support for the trials; and 3) identify and disseminate the best strategies for engaging health care systems as research partners to implement coordinated pain care programs. The CC also will serve as the central administrative resource for organizing the activities of the Coordinated Approaches to Pain Care Program.

Close interaction with NIH staff and the CC will be needed to accomplish the goals of this program.

NIH Pragmatic Trials Collaboratory Work Groups have been established by the CC and the NIH as the core collaborative activity of this program. The Work Groups provide a forum for discussion of challenges and solutions across projects and will guide harmonized and standardized policies and processes.Work Groups include: Electronic Health Records, Regulatory /Ethics, Biostatistics & Study Design, Health Care Systems Interactions, Implementation Science, Health Equity, and Patient Reported Outcomes (http://rethinkingclinicaltrials.org/cores-and-working-groups/).  Work Groups will comprise individuals from each of the Trials, the Coordinating Center, and NIH staff. This NOFO will support applications where PD/PIs  identify study staff or investigators that will participate in Collaboratory Work Groups.

A Steering Committee has been established by the CC to address issues that span all projects, provide input into the policies and processes of the NIH Pragmatic Trials Collaboratory, and assist in dissemination of policies and processes that enable research in healthcare systems. The Steering Committee will have at least one representative from each project, the Work Groups, the Coordinating Center, and NIH Program Officers and Project Scientists. All members are expected to participate in all Steering Committee activities. The combined vote of NIH membership may not exceed 40 percent at any time. NIH may convene an external panel of experts to provide advice on the overall program progress.

This NOFO will award 3 to 5 Individual Implementation Research Projects to a variety of HCSs where coordinated care does not exist or has limited uptake by patients.

This NOFO will prioritize HCSs that are:

• Private or Nonprofit HCSs with infrastructure and resources for delivery and coverage of coordinated care components through specialty care centers to provide comprehensive care.Private or Nonprofit HCSs with coverage for services provided in part through primary care and in part through referral to other specialty services within the HCS for integrated care.
• Public HCSs with capability for delivery of services in part through primary care and in part through referrals to other specialty services for integrated care (e.g., FQHCs)

Background

The aim of the HEAL Coordinated Approaches to Pain Care in Health Care Systems program is to establish a framework to deliver quality coordinated multidisciplinary pain management that integrates primary care and specialty care services within the infrastructure and resources of a variety of Health Care Systems. Participation in such studies will benefit the Health Care Systems by providing resources for implementation trials to embed evidence-based coordinated pain care practices into routine care.

The National Pain Strategy (NPS) https://www.iprcc.nih.gov/national-pain-strategy-overview/national-pain-strategy-report describes the need for coordinated evidence-based pain care and highlights many barriers that hinder its delivery. The NPS notes that in too many health care settings pain management is limited to pharmacological therapies through primary care or to incentivized interventions in specialty clinics that are based on practice experience rather than aligned with evidence-based practices best suited to meet the expected outcomes of the individual. In settings where integrated care is provided, it is often not informed by a comprehensive pain assessment, clinical evidence, or best practices and not coordinated across disciplines. The NPS also notes that whereas more studies on the effectiveness of integrated pain care are needed, further hurdles to quality pain coordinated care delivery exist. Access to care for some, especially health disparities populations, coverage for medications, interventions and services, and dissemination of best practices into health care settings all hamper quality care delivery and diminish health outcomes for those with pain.

The NPS recommends quality research on models of coordinated evidence-based care delivery and effective methods to incorporate them into practice settings. The benefits of engaging health care systems in implementation research include the existing infrastructure, large and diverse patient populations, availability of expertise across disciplines. The advantages of partnering health care systems with experience and expertise in implementation research with those that typically do not or have not participated in implementation research is the broader dissemination of coordinated care into both HCS.

The importance of engaging Health Care Systems in implementation research for best practices is reflected in enhancement and retention of quality care beyond the time frame of the research endeavor and the delivery of improved care to the general population and to health disparities populations. The benefits of participation in implementation research to the Health Care Systems include resources to improve their infrastructure to enhance routine care delivery, explore practices most effective and efficient to their health care model, and the potential cost-benefit to the HCS and potential for improved health outcomes of their community.

The biopsychosocial nature of pain highlights the need for coordinated and personalized care for those with complex chronic pain conditions who often have related comorbidities. Pain care is too often delivered as single modality through one setting, resulting in inadequate pain management and poor health outcomes. Coordinated pain care should optimize use of effective medications, procedures, physical function and psychological therapies, patient self-management strategies, and complementary approaches to manage pain. The care plan should be centered on patient goals and achieved by leveraging existing HCS resources delivered though a coordinated approach and supported by payor policies and guidelines.

In the context of this NOFO, coordinated care is that which is centered in primary care in consultation with appropriate specialty services available in the HCS. A comprehensive (AHRQ definition) coordinated approach provides appropriate components of coordinated pain care in a specialty clinic or rehabilitation setting in consultation with primary care. An integrated (AHRQ definition) coordinated approach provides support for primary care providers to interact with related care teams to enhance evidence-based coordinated care through referral to specialty care as needed. Primary care is an essential component of either approach.

In the context of this NOFO, implementation research is defined as research designed to determine how to apply an effective intervention within the resources of the HCS and to retain it beyond the time of the study. This NOFO will support implementation research that aims to consider the behavior of practitioners, support staff, patients, payers, and policymakers as key influencers on the adoption, implementation and sustainability of the evidence-based health interventions proposed in the study. This NOFO will support implementation research studies that do not assume that effective interventions can be integrated into any service setting and for consumer groups and populations without attention to local context, nor that a unidirectional flow of information (e.g., publishing a recommendation, trial, or guideline) is sufficient to achieve practice change.

In the context of this NOFO, populations with health disparities are those that experience a disproportionate share of chronic pain and other co-occurring chronic conditions, do not receive quality care, and/or have poor health outcomes.

This NOFO will support research areas such as:

• Clinical trials to evaluate implementation strategies to embed evidence-based approaches for coordinated pain care (integrated or comprehensive care) into HCS.
• Trials to evaluate strategies that enhance, increase the uptake of, or access to existing coordinated care pain programs for underserved populations.
• Trials to embed innovative approaches to optimize existing coordinated pain care models in an HCS: e.g., improve access to coordinated care, expand available services, enhance stakeholder engagement in developing care plans, or extend community partnerships for care delivery.

Research Objectives

This NOFO solicits applications for UG3/UH3 exploratory/developmental phased award cooperative agreements for large-scale implementation research trials. This NOFO will support applications in which thedesign of the proposed project maximizes external validity of the study, by testing generalizability, feasibility and sustainability of findings across the HCS and diverse patient populations.

This NOFO will support proposals for  implementation trials that meet the following objectives:

• Support coordination of appropriate interventions that are effective, apply broadly to diverse patient populations including those with greatest need and underrepresented populations and be suitable for the HCS with a goal of determining whether the approach and adds value to health care delivery. The question(s) being tested have a significant impact on care and care delivery within the participating HCS. 
• Intervention(s) are integrated with primary care, patient oriented, and can be reliably delivered by the HCS. Drugs, biologics, or devices that are part of the multidisciplinary care package, are legally marketed in the US, and used as approved/cleared for use by the US Food and Drug Administration.
• Intervention(s) are feasible in that they do not require a complex or unavailable structure for implementation or monitoring. System level interventions are particularly suitable.
• Project leverages resources available to the HCS.
• Study design incorporates rigorous controls that are prospectively identified. The design may incorporate novel randomization approaches.
• Proposed analytic plans address adequacy of sample size and study power; and employ analytic strategies relevant for such implementation study designs, especially those that propose cluster-randomized trials. Applicants can consult Collaboratory Biostatistical Guidance documents (https://rethinkingclinicaltrials.org/chapters/design/experimental-designs-randomization-schemes-top/experimental-designs-and-randomization-schemes-introduction/) and the NIH Research Methods Resources website on group- or cluster-randomized trials (https://researchmethodsresources.nih.gov/grt.aspx ) when developing pragmatic trial analytic plans.
• The study  identifies barriers to implementation and propose approaches to overcome them.
• The study population reflects the distribution of the condition under study in the US population per NIH requirements for gender and minority recruitment in the overall study population. There is strong scientific justification for any variables related to patient selection and ensure there are no intentional or unintentional exclusions based on risk, age, health literacy, expected adherence, or demographics.

This NOFO will support applications which include these items:

• A proposed coordinated care approach that is multidisciplinary and includes, at a minimum, an appropriate medication management program, psychological approaches and physical interventions. Additional interventions such as procedures and complementary interventions may be included.
• Utilization of rigorous methods and study design for an implementation trial.
• An implementation plan for embedding evidence-based models of coordinated pain care. A plan for service coverage within the HCS (leverage proposed CMS rule change for codes and coverage of comprehensive or integrated pain care programs).
• Inclusion of patients, providers, payors, and policymakers as stakeholders in study strategic planning, design, implementation, and evaluation.
• A plan for sustainability of the pain care model in the participating HCS after study completion, if the implementation strategies are effective and the intervention demonstrates effectiveness (as applicable).
• A diversity and inclusion plan for the population to be recruited.
• A plan to integrate primary care and specialty care.
• A plan for collaboration and participation in the coordinating center activities.
• Inclusion primary care providers in either a comprehensive or integrated care strategy to oversee coordinated care. 

Research Mechanisms and Program Governance

The awards funded under this NOFO will be cooperative agreements (see Section VI.2 Cooperative Agreement Terms and Conditions of Award). Close interaction with the NIH, the recipients  of the individual program trials, and the CC investigators will be needed to accomplish the goals of this program. Trials selected for the Coordinated Approaches to Pain Care will have administering NIH IC officials who will be partners in the Coordinated Approaches to Pain Care Program. They will be phased awards with a one-year planning phase (UG3) and a two-to-four-year trial conduct phase (UH3). Activities in both phases will depend on the specific study (e.g. disease domains, type of interventions, experimental design, randomization strategy and proposed outcome measures).

This NOFO will support applications with UG3 planning phases that include , but are not limited to, these activities: :

• Identify project staff that will participate in work groups established by the coordinating center to develop guidelines and practices to be implemented across projects.
• Implement approved guidelines and practices for electronic data extraction and quality control methods and tools and for electronic data sharing, to include developing and validating all electronic data methods and tools.
• Assess adequacy and finalize clinically relevant outcome measures in coordination with the other recipients  and with oversight from the coordinating center and other teams. Awarded applicants will work with other recipients  and work with the CC and NIH to develop metrics for resource utilization for planning and implementing trials.
• Refine study design elements with guidance from NIH and the CC including sample size, site heterogeneity, and implementation timetable.
• Develop detailed plans for site implementation, including site staff, method of identification, randomization (as applicable) and participant recruitment and acquisition and administration/implementation of the intervention if applicable.
• Address all ethical issues and issues related to human subject safety oversight for the Project, including development of informed consent documents or opt-out consent if applicable, and finalizing site of IRB review. Applicants should propose a single IRB or centralized IRB approach for trial oversight to facilitate both appropriate and timely study conduct.
• Address all potential regulatory elements of the proposed trial (if applicable).
• Develop a detailed budget for conduct and completion of the Project, including preparation of a final planning phase report.
• Finalize detailed plans for data coordination and quality control for the UH3 phase.

The UH3 Project Trial Conduct Phase (UH3): The objective of the UH3 trial conduct phase is to conduct the Project in accordance with activities planned in the UG3 phase. Activities will depend upon the study, but in general this NOFO will support applications with the following goals:

• Conduct all aspects of the proposed implementation or effectiveness/implementation trial including the recruitment of proposed sample sizes of patient cohorts, practice sites, and/or clinicians; the execution of the intervention and its delivery within the HCS, and the assessment of outcomes.
• Provide complete assessment of all issues related to patient, clinician and site identification, and EHR tools used in these steps.
•  Provide definitive information about the execution of the intervention at all sites.
•  Assess fidelity to the intervention.
•  Provide detailed and definitive testing of the validity of methods used for monitoring and outcome assessment.

Go/no go criteria for UG3/UH3 Transition and milestones for UH3

This NOFO will utilize a two-phase cooperative agreement mechanism consisting of a start-up/planning phase up to one year (UG3) and an implementation or hybrid effectiveness/implementation trial execution phase (up to 4 years UH3). This NOFO will support applications that include well-defined Phase 1 go/no go criteria and phase 2 annual milestones with Phase 1 (UG3) “go/no go criteria” that include steps needed prior to trial initiation that will be completed prior to approval and funding to transition to the trial conduct phase (UH3). This NOFO will support applications that include clearly defined milestones for each year of the UH3 phase. A milestone is defined as a scheduled event in the project timeline, signifying the completion of a major project stage or activity. Annual milestones for the UH3 study conduct phase may be revised as appropriate to refine the study design and protocol during the UG3 planning year. The PD/PI and NIH staff will negotiate a final list of milestones for each year of support prior to releasing an award.

The UG3 planning phase go/no go criteria are used to assess progress needed to move forward to phase 2 and might include: study protocols are developed, stakeholder engagement approaches are developed, training of intervention providers is implemented, comparison group providers or other resources are planned. All regulatory approvals should be obtained prior to the end of the UG3 award. Two months prior to the end of the UG3 planning phase, the applicant will submit a detailed transition request for approval to move forward to the UH3 Project trial conduct phase. This request will be reviewed administratively by NIH to determine whether or not go criteria and milestones have been met to allow the UH3 trial conduct phase will be awarded. Initial funding of the UG3/UH3 Phased cooperative agreement does not guarantee support of the UH3 Project trial conduct phase.

The UH3 annual milestones are used to assess whether satisfactory progress has been made for continuation of funding over the timeline of the trial. Annual UH3 milestones might include recruitment goals, data accrual, embedding resources for service delivery in the partner HCS, program participation and contributions, and other timely and essential study requirements. NIH staff will closely monitor progress of milestones, accrual, and safety.

Types of Clinical Trials Not Responsive to this NOFO

This NOFO deems applications proposing activities such as those below as non-responsive, and applications proposing such activities will not be reviewed: 

• Applications that lack well-defined go/no go criteria with yes/no considerations to be completed in Phase 1 (UG2) to transition to phase 2 (UH3) and well-defined milestones for each year of the proposed trial.
• Applications that fail to propose coordinated pain care that is centered in the primary care setting.
• Applications that do not include a multidisciplinary team and/or lack an implementation scientist.
• Applications that do not include multidisciplinary coordinated pain management programs that include at a minimum, an appropriate medication management program, psychological approaches and physical interventions.
• Applications that do not propose implementation of multidisciplinary care.
• Applications that do not propose aims to assess implementation outcomes.

Clinical Trial Accrual:  

This NOFO will support applications that include a series of milestones for completion of the clinical trial and provide contingency plans to proactively confront potential delays or disturbances in attaining the milestones. Continuation of the award is conditional upon satisfactory progress, availability of funds, and scientific priorities of the HEAL Initiative. If, at any time, recruitment falls significantly below the projected milestones for recruitment, NIH will consider ending support and negotiating an orderly phase-out of the award. NIH retains the option of periodic external peer review of progress. NIH program staff will closely monitor progress at all stages for milestones, accrual, and safety. 

Research Areas of Interest

For each participating NIH IC, examples of potential research questions that could be addressed by implementation trials and would be responsive to this NOFO are outlined below. Potential applicants are urged to contact NIH Scientific/Research Staff to ensure that proposed studies are responsive to this NOFO.

HEAL Specific Requirements:

Promoting Diversity

Applicants are encouraged to recruit prospective program participants from diverse backgrounds, including those from underrepresented groups in the biomedical research workforce. Research shows that diverse teams working together and capitalizing on innovative ideas and distinct perspectives outperform homogeneous teams. Scientists and trainees from diverse backgrounds and life experiences bring different perspectives, creativity, and individual enterprise to address complex scientific problems. There are many benefits that flow from a diverse NIH-supported scientific workforce, including: fostering scientific innovation, enhancing global competitiveness, contributing to robust learning environments, improving the quality of the research, advancing the likelihood that underserved or health disparity populations participate in, and benefit from health research, and enhancing public trust. In spite of tremendous advancements in scientific research, information, educational and research opportunities are not equally available to all. Please refer to Notice of NIH's Interest in Diversity NOT-OD-20-031 for more details. Please note that consistent with NIH practice and applicable law, funded programs may not use the race, ethnicity, or sex of prospective program participants or faculty as an eligibility or selection criteria. The race, ethnicity, or sex of candidates will not be considered by NIH in the application review process or when making funding decisions. 

HEAL Scientific Meeting

The NIH HEAL Initiative will require a high level of coordination and sharing between investigators. This NOFO will support NIH HEAL Initiative recipients that will cooperate and coordinate their activities after awards are made by participating in Program Director/Principal Investigator (PD/PI) meetings, including an annual HEAL Scientific Meeting, and other activities. In addition, travel to attend an annual meeting one-and-a-half-day NIH Pragmatic Trials Collaboratory program meetings each year in the greater Washington D.C. area is expected.

Common Data Elements (CDEs)

The HEAL Clinical Pain Common Data Element (CDE) Initiative provides an unprecedented opportunity for the pain research community to access quality and meaningful data across pain conditions, diverse populations, and multiple interventions. The HEAL CDE initiative aims to facilitate cross-study comparisons, improve interpretability of findings for patient-reported outcomes, and improve the ability to compare results across trials to quantify the impact of interventions. For studies involving human subjects, this NOFO will support projects that use the HEAL Clinical Pain Core CDEs, which include measures within ten pain domains and are specific to either adult or pediatric populations and acute or chronic pain conditions. The domains include pain intensity, pain interference, physical functioning/quality of life, sleep, pain catastrophizing, depression, anxiety, treatment satisfaction, quality of life, and a substance use screener (HEAL CDE Program). For studies that use additional pain screening tools, this NOFO will support studies that select from a comprehensive set coded through HEAL or that submit their tools for coding to comply with HEAL pain data harmonization. This NOFO will support studies where outcome measures specific to clinical pain are validated measures appropriate for the pain condition.

Rigor and Transparency

NIH strives for rigor and transparency in all research it funds. For this reason, this NOFO explicitly emphasizes the NIH application instructions related to rigor and transparency (https://grants.nih.gov/policy/reproducibility/guidance.htm) and provides additional guidance to the scientific community (https://www.ninds.nih.gov/Funding/grant_policy). For example, this NOFO supports applications in which the biological rationale for the proposed experiments are based on rigorous and robust supporting data, which means that data are collected via methods that minimize the risk of bias and be reported in a transparent manner. If previously published or preliminary studies do not meet these standards, this NOFO will support applicants that address how the current study design addresses the deficiencies in rigor and transparency. This NOFO support proposed experiments that are  designed in a manner that minimizes the risk of bias and ensures validity of experimental results.

This NOFO intends to support applications with proposed clinical trials that are based on robust and rigorous supporting data (e.g., from non-clinical in vivo and/or in vitro studies or preliminary clinical studies) that demonstrate that there is an adequate scientific foundation to justify the proposed trial. This NOFO supports trial designs that also use rigorous and transparent approaches.
 

See Section VIII. Other Information for award authorities and regulations.

Investigators proposing NIH-defined clinical trials may refer to the Research Methods Resources website for information about developing statistical methods and study designs.

Section II. Award Information

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this NOFO.

Section III. Eligibility Information

1. Eligible Applicants

All organizations administering an eligible parent award may apply for a supplement under this NOFO.

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)

Local 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)

Federal Government

• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Other

• 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

Non-domestic (non-U.S.) Entities (Foreign Organizations) are not eligible to apply.

Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are not allowed. 

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the How to Apply - 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. Failure to complete registrations in advance of a due date is not a valid reason for a late submission, please reference NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications for additional information. 

• 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.
  • Unique Entity Identifier (UEI) - A UEI is issued as part of the SAM.gov registration process. The same UEI must be used for all registrations, as well as on the grant application.
• eRA Commons - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their Grants.gov registration; 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 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.

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with their organization to develop an application for support. Individuals from diverse backgrounds, including underrepresented racial and ethnic groups, individuals with disabilities, and women are always encouraged to apply for NIH support. See, Reminder: Notice of NIH's Encouragement of Applications Supporting Individuals from Underrepresented Ethnic and Racial Groups as well as Individuals with Disabilities, NOT-OD-22-019.

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 How to Apply - Application Guide.

2. Cost Sharing

This NOFO does not require cost sharing as defined in the NIH Grants Policy Statement Section 1.2 Definition of Terms.

3. Additional Information on Eligibility

Number of Applications

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

The NIH will not accept duplicate or highly overlapping applications under review at the same time, per NIH Grants Policy Statement Section 2.3.7.4 Submission of Resubmission Application. 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 NIH Grants Policy Statement 2.3.9.4 Similar, Essentially Identical, or Identical Applications).

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 NOFO. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide except where instructed in this notice of funding opportunity to do otherwise. Conformance to the requirements in the How to Apply - Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

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:

Linda Porter, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-346-3266
Email: porterl@ninds.nih.gov

All page limitations described in the How to Apply – Application Guide and the Table of Page Limits must be followed.

For this specific NOFO, the Research Strategy section is limited to 12 pages, divided between the UG3 and UH3 phases of the project.

The following section supplements the instructions found in the How to Apply – Application Guide and should be used for preparing an application to this NOFO.

All instructions in the How to Apply - Application Guide must be followed.

All instructions in the How to Apply - Application Guide must be followed.

All instructions in the How to Apply - Application Guide must be followed.

All instructions in the How to Apply - Application Guide must be followed.

Biosketches should reflect the PD(s)/PI(s) and key personnel's expertise in design and conduct of large-scale clinical or implementation trials within multiple HCS including using electronic health records for recruitment and outcomes assessment. The experience of the investigative team with successful recruitment and retention of participants should be described.

R&R Budget

All instructions in the How to Apply - Application Guide must be followed.

Budgets for both phases (UG3/UH3) must be included; the UH3 budget will undergo reassessment during the UG3 planning phase.

Application budgets must include a minimum effort for the PD/PI of 2.4 person months to the project. If a project includes multiple PDs/PIs, the total annual PD/PI effort must be at least 2.4 person months.

Application should have an appropriate mix of time allocated for senior and junior scientists to ensure the successful conduct of the study. Budgeted effort of other personnel should be appropriate to the needs of the project.

The budget should include participating personnel in the HCS with expertise relevant to the project, which might include electronic health record IT specialists, clinical investigators and staff with expertise in the administrative aspects of clinical trials oversight.

Applications should budget for study personnel to participate in each of the Work Groups.

The applicant is expected to include funds for the project PD/PI and key personnel to attend one Coordinated Approaches to Pain Care program meeting in the first year and an annual meeting in subsequent years in the Bethesda MD area and one face-to-face NIH HEAL Investigator meeting to be held in the Bethesda, Maryland or Washington, DC general geographic area.

Applicants should include funds for strategies for stakeholder engagement and strategies to recruit and retain diverse populations.

R&R Subaward Budget

All instructions in the How to Apply - Application Guide must be followed.

All instructions in the How to Apply - Application Guide must be followed.

All instructions in the How to Apply - Application Guide must be followed, with the following additional instructions:

The Coordinated Care research projects will be interacting with their partner Health Care System, the collective set of awarded projects, the Coordinating Center, and NIH staff in this effort.

• The application must provide information regarding the interactions with other awarded projects and the CC as they plan and implement their studies.
• The application must provide details of the study design and biostatistical assumptions of the trials during their planning phase; plans for site implementation, resource needs, test data extraction methods for patient identification and outcome assessments, and plans for all aspects of ethical and regulatory oversight and protection of human subjects.
• The application must describe the interventions proposed and justify their selections based on effectiveness of the interventions and feasibility of implementation given the resources and practices of their partnering HCS.
• Applicants must describe processes through which the resources and interventions developed through the project will be made available to the community after the period of support ends.
• Applicants must indicate their willingness to cooperate with other awarded project teams supported by this program.
• Applicants must describe their prior experience working collaboratively in research consortia and other collaborative projects to accomplish shared goals.
• The application must provide rationale for the HCS selected and description how its resources will be leveraged and integrated to complete the project.
• Plans for stakeholder engagement should be described.

To distinguish between the two phases, applicants must specify separate UG3 and UH3 information in each subsection (Specific Aims and Research Strategy) of the PHS 398 Research Plan as appropriate. Activities in both phases will depend on the specific study (e.g. disease domains, type of interventions, experimental design, randomization strategy and proposed outcome measures).

In preparing the application, investigators should consider the fact that applications will be assigned a single impact score for both UG3 and UH3 phases.

Specific Aims: Applicants must address the scientific questions posed, what will be done to address the questions during the proposed funding periods, and the impact of addressing the research question on public health. Specific aims must be scientifically appropriate for the distinct phases of the project. Include separate specific aims, within the designated page limit, for the UG3 and UH3 phase, and clearly label them as UG3 specific aims or UH3 specific aims.

Research Strategy:

Applicants must first describe the UG3 Phase and then the UH3 Phase. The Research Strategy section must have a clear demarcation of the UG3 and UH3 phases of the application. It is not necessary to repeat background information or details of methods in the UH3 portion that were provided in the UG3 portion. The UH3 Phase must be described in sufficient detail to permit reviewers to assess feasibility, significance, and innovation of the proposed work and the strength of the experimental design. Address how the research questions serve the goals of the overall program and address a major public health issue.  The application must describe details for the proposed trial including design, projections for recruitment, attrition, effect size estimations, and resources and approaches for implementation. Applicants must describe how the approaches, measures, design, and outcomes proposed are aligned with resources of the HCS partners and expectations for uptake of successful outcomes into the services provided by the HCS. A plan for sustainability of the interventions in the partner HCS and the generalizability to a broader set of HCS must be described.

Plans on the approach to integrate primary and specialty care must be clearly presented. The roles of patients and providers in establishing pain care plans, service delivery, and outcomes assessments across the continuum of care must be described. The selection of intervention(s) to evaluate and implement for coordination of care must be justified and the feasibility of their implementation in the HCS partners must be described. The evidence-base for the model of care to embed in the study must be included in the application.

The application must include a section (see other project materials) of proposed UG3 go/no-go transition criteria and UH3 annual milestones which are well described, quantifiable, and scientifically justified to allow an assessment of progress. For UG3 go/no go criteria, applicants must delineate what they propose to achieve to proceed to the UH3 phase. These criteria must include a timeline, a discussion of the suitability of the criteria for assessing success in the UG3 Phase and implications of successful completion of these criteria for the proposed UH3 Phase. Annual milestones, with interim assessment timelines for the Project trial conduct phase (UH3) also must be included in the application. It is understood however, that timelines and milestones for conduct of the trial in the UH3 phase that are proposed in the application will evolve as activities in the UG3 phase progress and as appropriate to design changes. 

Applicants must address how they will adhere to the NIH Policy on Good Clinical Practice Training. This policy establishes the expectation that all NIH-funded investigators and staff who are involved in the conduct, oversight, or management of clinical trials must be trained in Good Clinical Practice (GCP), consistent with principles of the International Conference on Harmonization (ICH) E6 (R2) The principles of GCP help assure the safety, integrity, and quality of clinical trials. This Policy applies to NIH-funded investigators and clinical trial site staff who are responsible for the conduct, management and oversight of NIH-funded clinical trials (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-16-148.html).

Rigor and Transparency: 

NINDS urges investigators to follow the NIH guidance for rigor and transparency in grant applications (https://grants.nih.gov/policy/reproducibility/guidance.htm) and additionally recommends the research practices described at https://www.ninds.nih.gov/Funding/grant_policy. This will ensure that robust experiments are designed, potential experimenter biases are minimized, results and analyses are transparently reported, and results are interpreted carefully. These recommended research practices include, where applicable, expressing clear rationale for the chosen model(s) and primary/secondary endpoint(s), describing tools and parameters clearly, blinding, randomizing, ensuring adequate sample size, pre-specifying inclusion/exclusion criteria, appropriately handling missing data and outliers, implementing appropriate controls, preplanning analyses, and using appropriate quantitative techniques. It is also strongly recommended to indicate clearly the exploratory vs. confirmatory components of the study, consider study limitations, and plan for transparent reporting of all methods, analyses, and results so that other investigators can evaluate the quality of the work and potentially perform replications. Investigators must indicate whether data presented or cited in the application as key support for the proposed work were collected, analyzed, and reported in a rigorous and transparent manner as indicated above. A plan to address any ambiguity, weaknesses, or limitations in the prior research must be included in the application. Proposed experiments mus similarly adhere to these high standards of rigor and transparency.

Applicants must describe the rigor, robustness, and transparency of supporting data that are being used to justify the proposed trial and address any gaps identified. For all clinical trials, the rationale for the trial design, population(s) and hypotheses being tested, and control groups must be described. Potential biases and/or challenges in the study design and must should be identified and addressed.  For efficacy or effectiveness (typically Phase III or later) clinical trials, the proposal must account for clinical relevance of the expected effect size and include measures, such as blinding and randomization, to reduce the risk of systematic biases.  

This grant is a cooperative agreement and will include milestones. Milestone reports must describe how measurable outcomes will be collected using rigorous and transparent experimental approaches. These approaches include, but are not limited to, randomization, blinding, use of statistically adequate sample sizes with biologically relevant effect sizes, minimization of potential bias, independent replication, and adequate reporting of experimental details and results as described at https://www.ninds.nih.gov/Funding/grant_policy

Letters of Support: Applications must  include a strong letter of support from the HCS that states their commitment to the proposed research and outlines how the project fits with organizational priorities, the quality of the proposed resources and the commitment of their staff to the project. The letter must provide a description of how the project would directly impact delivery of healthcare within their organization and indicate level of intention to sustain the intervention(s) based upon results. The application must include letters from the officials responsible for intellectual property issues at the applicant institutions (including sub-contractor institutions) stating that the institution supports and agrees to abide by the Resources Sharing Plan and the Software Sharing Plan put forth in the application. These letters must be clear expressions of commitment consistent with achieving the goals of the program.

Resource Sharing Plan:

Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the How to Apply - Application Guide. 

The following modifications also apply:

• Applicants should provide a description of the resources that will be made broadly available including policies, practices, materials, and tools to facilitate collaboration, reuse, and replication of the project. Describe any plans to disseminate toolkits or other resources developed for implementation trials. 

Other Plan(s):

Note: Effective for due dates on or after January 25, 2023, the Data Management and Sharing Plan will be attached in the Other Plan(s) attachment in FORMS-H application forms packages.

All instructions in the How to Apply - Application Guide must be followed, with the following additional instructions:

Data Management and Sharing Plan 

Note: The NIH Policy for Data Management and Sharing is effective for due dates on or after January 25, 2023.

Consistent with the NIH Policy for Data Management and Sharing, when data management and sharing is applicable to the award, recipients will be required to adhere to the Data Management and Sharing requirements as outlined in the NIH Grants Policy Statement. Upon the approval of a Data Management and Sharing Plan, it is required for recipients to implement the plan as described.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions: 

HEAL Data Sharing Requirements

NIH intends to maximize the impact of HEAL Initiative-supported projects through broad and rapid data sharing.  All HEAL Initiative award recipients, regardless of the amount of direct costs requested for any one year, are required to comply with the HEAL Public Access and Data Sharing Policy. HEAL award recipients must following all requirements and timelines developed through the HEAL Initiative Data Ecosystem (https://heal.nih.gov/about/heal-data-ecosystem), as described in HEAL’s compliance guidance (See “Already Funded” section: https://heal.nih.gov/data/complying-heal-data-sharing-policy):  
 

1. Select a HEAL – Compliant data repository (https://www.healdatafair.org/resources/guidance/selection)  

Data generated by HEAL Initiative-funded projects must be submitted to study-appropriate, HEAL-compliant, data repositories to ensure the data is accessible via the HEAL Initiative Data Ecosystem.

Some repositories require use of specific data dictionaries or structured data elements, so knowing your repository’s requirements up front can help reduce the burden of preparing data for submission.

HEAL-funded recipients  must follow requirements for selected repository 

2. Within one year of award, register your study with the HEAL platform (https://heal.github.io/platform-documentation/study-registration/) 

This process will connect the Platform to information about your study and data, including metadata, and identify the selected repository. HEAL requests initial submission within one year of award, with annual updates, and to be updated in accordance with any release of study data.

3. Within one year of award, submit HEAL-specific study-level metadata. 

Some of the required study-level metadata (https://github.com/HEAL/heal-metadata-schemas/blob/main/for-investigators-how-to/study-level-metadata-fields/study-metadata-schema-for-humans.pdf) will be auto-populated as part of the registration process. 
 

4. Submit data and metadata (and code, if applicable) to HEAL-Compliant repository  

At the completion of the study and/or when prepared to make the final data deposits in the repositor(ies) of choice, ensure your study registration (https://heal.github.io/platform-documentation/study-registration/) is complete.

Submit data dictionaries to the HEAL data ecosystem, if applicable.

The NIH HEAL Initiative expects data sharing timelines to align with timeline requirements stated in the Final NIH Policy for Data Management and Sharing (NOT-OD-21-013).

6. Additional Requirements for HEAL Initiative studies conducting clinical research or research involving human subjects.

These studies must meet the following additional requirements: 

HEAL Initiative trials that are required to register in clinicaltrials.gov should reference support from and inclusion in the HEAL Initiative by including the standardized terms “the HEAL Initiative (https://heal.nih.gov/)” in the Study Description Section.

All new HEAL clinical pain studies are required to use core questionnaires required by the HEAL Clinical Data Elements (CDE) Program (https://heal.nih.gov/data/common-data-elements). Outside of the core questionnaires, studies should select questionnaires from among the repository of supplemental questionnaires that are already being used by other HEAL clinical pain studies. The program has created the CDE files containing standardized variable names, responses, coding, and other information for all of these questionnaires The program has also formatted the case-report forms in a standardized way that is compliant with accessibility standards under Section 508 of the Rehabilitation Act of 1973 (29 U.S.C § 794 (d); https://www.govinfo.gov/content/pkg/USCODE-2011-title29/html/USCODE-2011-title29-chap16-subchapV-sec794d.htm) which “require[s] Federal agencies to make their electronic and information technology accessible to people with disabilities.” 

Studies that wish to use questionnaires not already included in the HEAL CDE repository should consult with their program official and the HEAL CDE team. New questionnaires will be considered for inclusion in the repository on a case-by-case basis and only when appropriate justification is provided.   

HEAL Initiative clinical studies that are using copyrighted questionnaires  are required to obtain licenses for use prior to initiating data collection. Licenses must be shared with the HEAL CDE team and the program officer prior to use of copyrighted materials. For additional information, visit the HEAL CDE Program (https://heal.nih.gov/data/common-data-elements). 

To the extent possible, all other (non-pain) HEAL studies conducting clinical trials or research involving human subject are expected to use questionnaires by the HEAL Clinical Data Elements (CDE) Program (https://heal.nih.gov/data/common-data-elements) if applicable and relevant to their research. 

To the extent possible, HEAL recipients  are expected to integrate broad data sharing consent language into their informed consent forms.

Additional details, resources, and tools to assist with data related activities can be found at https://www.healdatafair.org/.Budgeting guidance for data sharing can be found in NOT-OD-21-015 and the NIH Scientific Data Sharing site.

All data collected as part of the NIH HEAL Initiative are so collected under a Certificate of Confidentiality and entitled to the protections thereof. Institutions who receive Data and/or Materials from this award for performance of activities under this award are required to use the Data and/or Materials only as outlined by the NIH HEAL Initiative, in a manner that is consistent with applicable state and federal laws and regulations, including any informed consent requirements and the terms of the institution’s NIH funding, including NOT-OD-17-109 and 42 U.S.C. 241(d). Failure to adhere to this criterion may result in enforcement actions. 

Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the How to Apply - Application Guide.

• Only blank questionnaires, surveys , or consent forms may be included in the Appendix.

When involving human subjects research, clinical research, and/or NIH-defined clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the How to Apply - Application Guide, with the following additional instructions:

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 How to Apply - Application Guide must be followed.

Section 2 - Study Population Characteristics

2.4 Inclusion of Women and Minorities

Describe strategies for outreach to minorities and women.

2.5 Recruitment and Retention Plan

Describe the following: 1) the planned recruitment methods, including use of contact lists (participants and/or sites), databases or other pre-screening resources, advertisements, outreach, media / social media and referral networks or groups; 2) if there are known participant or study-related barriers to accrual or participation (based on literature or prior experience), please list these barriers and describe plans to address them to optimize success; 3) contingency plans for participant accrual if enrollment significantly lags behind accrual benchmarks; 4) participant retention and adherence strategies; and 5) possible competition from other trials for study participants. Applicants should describe a plan for diversity and inclusion in the study population. Budget requests should include the resources needed to promote diversity and inclusion.

Applicants should provide strong evidence of the availability of appropriate institutional resources, and suitable patient populations, providers, clinics, or facilities (depending on unit of randomization). Documentation of availability of eligible participants, clinic sites, or unites of randomization, presented in tabular format should be provided. The application should include relevant information that addresses the feasibility of recruiting participants who are eligible for the pragmatic or implementation trial. Applicants should provide evidence that each recruiting component /HCS in the trial has access to a sufficient number of participants who meet the eligibility criteria as defined in the submitted protocol. For multisite applications, information should be provided for each participating site/HCS.

2.7 Study Timeline

Include a table or graph of the overall study timeline. This is expected to be a visual representation (such as a Gantt chart) of core milestones and key project management activities. A narrative is not expected in this section.

The study timeline should include core criteria and milestones that need to be met throughout the life cycle of the clinical trial (to include both the UG3 and UH3 phases) to ensure its success, and the subtasks that will be used to reach the milestones. In the timeline, the study duration is expected to be displayed in months. The timeline should include, but is not limited to, the following:

(a) When the study opens to enrollment
(b) When core milestones (see below) are met
(c) What subtasks are needed to reach the core milestones
(d) When final transfer of the data will occur
(e) When analysis of the study data will occur
(f) When the primary study manuscript will be submitted for publication

Section 3 - Protection and Monitoring Plans

3.3 Data and Safety Monitoring Plan

In addition to the NIH application requirements for data and safety monitoring for clinical trials, applicants should refer to NIH’s policy on data and safety monitoring (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html).

Section 4 - Protocol Synopsis

4.1 Study Design

4.1.a. Detailed Description
Describe the protocol to be followed in each arm of the trial. Include a brief description of how the trial will standardize the intervention and whether there are any plans to intervene to improve adherence to the intervention at the sites. Specify concomitant interventions, if applicable. Describe the proposed experimental design, including a discussion of the clinical trial design and the rationale for the particular design chosen (pragmatic, explanatory, cluster-randomized, adaptive, etc.).

4.7 Dissemination Plan
Describe how the investigators will facilitate and support timely publication and dissemination of trial information to clinicaltrialsv.gov. .

Section 5 - Other Clinical Trial-related Attachments

5.1 Other Clinical Trial-related Attachments

The following attachments must be included as a part of the cooperative agreement application. Attachments permit expansion of certain elements that cannot be appropriately described in the Research Strategy. All attachments listed below must be provided or the application will not be peer reviewed.

1. Clinical Trial Experience

Applicants must provide a detailed table listing the characteristics of trials that demonstrate Key Personnel experience in trial coordination in the last 5 years. The table must be provided as an attachment called "Clinical Trial Experience.pdf", appended with 1, 2, 3, etc. as needed, and must not exceed 3 pages.

The table columns should include:

• Clinical trial title
• Applicant's role in the trial
• A brief description of the trial design
• Planned enrollment
• Actual enrollment
• Number of sites
• Whether the trial(s) was/were completed on schedule or not
• Publication reference(s)

2. Milestone Plan

Applicants must be provided as an attachment called "Milestone Plan.pdf" and must not exceed five pages.

The Plan must include proposed UG3 go/no-go transition criteria and UH3 annual milestones with an interim assessment timeline which are well described, quantifiable, and scientifically justified to allow an assessment of progress. For UG3 go/no go criteria, applicants should delineate what they propose to achieve to proceed to the UH3 phase. These criteria should include a timeline, a discussion of the suitability of the criteria for assessing success in the UG3 Phase and implications of successful completion of these criteria for the proposed UH3 Phase. Annual, with interim assessment timelines for the Project trial conduct phase (UH3) also must be included. All applicants should use the following definition of a milestone in their application: a scheduled event in the project timeline that signifies the completion of a major project stage or activity. The Terms and Conditions under this NOFO will include a milestone plan that is mutually agreed upon by the investigators and NIH.

Delayed Onset Study

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 How to Apply - Application Guide must be followed.

All instructions in the How to Apply - Application Guide must be followed.

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

See Part 2. 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

Part I. 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 Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications.

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 How to Apply – Application Guide.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

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 Section 7.9.1 Selected Items of Cost.

Applications must be submitted electronically following the instructions described in the How to Apply - 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 form. 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 NOFO for information on registration requirements.

The applicant organization must ensure that the unique entity identifier provided on the application is the same identifier used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the How to Apply - 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.

Applicants are required to follow the instructions for post-submission materials, as described in the policy

All post-submission materials must be received by the Scientific Review Officer (SRO) no later than 30 calendar days prior to the peer review meeting. In addition to the NIH policy allowed post-submission materials in NOT-OD-19-083, the follow post-submission materials are allowed:

• Updated Clinical Trial Experience Table (e.g. due to updated enrollment numbers, publication of trial results, or newly started clinical trials)
• Updated Milestone Plan (e.g. due to the hiring, replacement, or loss of an investigator; change to health care systems participating in the trial; or change in electronic health record or IT infrastructure)

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.

For this particular announcement, note the following: This NOFO includes Additional Review Criteria on Go/no go transition criteria and annual milestones, which require comment by reviewers and which are to be considered when determining the overall impact score.

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.

Overall Impact

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

Scored Review Criteria

Reviewers will consider each of the review criteria below in the determination of scientific merit and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

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?

In addition, for applications involving clinical trials

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?

Specific to this NOFO:

How likely is it that the study achieve effective strategies at the health care system level to address a clinical issue of significance?

How feasible is the  project plan to enhance coordination of pain care planning, service delivery and outcomes assessment that is patient centered, feasible, and will benefit stakeholders (patients, providers, payers, HCS)?

How feasible is the plan to embed coordinated care into the HCS and how strong is its potential to be sustainable beyond the duration of the study?

How compelling is the rationale that study interventions will provide clinically meaningful outcomes for stakeholders (patients, providers, payers, HCS)?

How strong is the likelihood that the planning activities and trial conduct will provide advances in the ability to perform large-scale implementation studies?

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?

In addition, for applications involving clinical trials

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?

Specific to this NOFO:

How strong is the justification that the investigators have experience in partnering and interacting with other teams in large scale projects?

How well does the application describe willingness and approaches to participate in activities across the program (ie with all awarded projects) and the CC?  

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?

In addition, for applications involving clinical trials

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?

Specific to this NOFO:

Does the application describe novel strategies to leverage resources and expertise between partner HCS?

Are novel approaches to embed enduring interventions into HCS generalizable to other HCS?

Is the plan to coordinate pain care across services (primary to specialty care) feasible and creative?

Are the means to assess health outcomes for patients and benefits to the HCS evident?

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?

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?

In addition, for applications involving clinical trials

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?

Specific to this NOFO: 

For studies that propose to improve adherence to established practice guidelines, how strong is the evidence for the guidelines that are accepted practice guidelines? How does the implementation plan align with the resources of the HCS partners?

How reasonable are the projections for recruitment, engagement, attrition, and effect size estimations based on the proposed HCS settings?

How well does the application describe approaches proposed to overcome barriers to research in the HCS setting?

How feasible is the approach to enhance coordinated care centered in primary care?

Rigor and Transparency

Does the proposed research incorporate adequate methodological rigor where applicable, including, but not limited to, clear rationale for the chosen model(s) and primary/secondary endpoint(s), clear descriptions of tools and parameters, blinding, randomization, adequate sample size, pre-specified inclusion/exclusion criteria, appropriate handling of missing data and outliers, appropriate controls, preplanned analyses, and appropriate quantitative techniques? Do the applicants clearly indicate the exploratory vs. confirmatory components of the study, consider study limitations, and plan for transparent reporting of all methods, analyses, and results so that other investigators can evaluate the quality of the work and potentially perform replications?

For clinical trials, is the scientific rationale of the proposed study based on well-designed, rigorous, and transparent previous preclinical and/or clinical research? Were any gaps in the rigor, robustness, or transparency of prior research identified, and, if so, how well were they addressed? Does the applicant describe potential biases and/or challenges in the study design or protocol and how they will be addressed? Is the proposed study design justified and appropriate, adequately controlled, and powered to address primary and secondary outcome variable(s)/endpoints? If applicable, will those variables/endpoints be clear, informative, and relevant to the population and hypothesis being tested? Are the study population(s) (i.e., gender, age, demographic group), proposed intervention arms and/or dosage, and duration of the trial appropriate and well justified? Is there a compelling rationale for the chosen subjects, endpoints, and statistical methods? For efficacy or effectiveness (typically Phase III or later) clinical trials, does the proposal account for clinical relevance of the expected effect size, and do the methods used to assign participants and deliver interventions properly apply blinding, randomization, controls, and approaches for handling missing data and outliers?

Do the milestones include measurable outcomes that will be collected using rigorous and transparent experimental approaches, including randomization, blinding, use of statistically adequate sample sizes with biologically relevant effect sizes, minimization of potential bias, independent replication, and adequate reporting of experimental details and results?

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?

In addition, for applications involving clinical trials

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?

Specific to this NOFO:

Does the application provide sufficient rationale for the HCS partners selected for the Project?

Is commitment to the project evident from both HCS partners?

Has at least one HCS partner successfully conducted clinical studies, such that there are sufficient infrastructure and expertise to implement the proposed implementation trial within both HCS partners?

Do both partner HCS have resources to implement service delivery that aligns with the proposed intervention?

Does the application indicate a commitment from the HCS partners to collaborate with workgroups across the program and the CC?

Is there a plan to leverage and coordinate resources across the partner HCS that will provide an environment supportive of the study goals?

Specific to this NOFO:

Is adherence to the NIH Policy on Good Clinical Practice Training adequately described?

Additional Review Criteria

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

Specific to this NOFO:

Go/no go criteria for UG3 phase 1

Are go/no go criteria for the UG3 appropriate for the UG3 phase needs and timeline (1 year or less)? Are these criteria sufficient to support a transition decision to fund/not fund a UH3 phase 2?

Milestones for UH3 phase 2

Are UH3 clinical trial annual milestones and interim assessment timelines clearly defined?

Are the milestones feasible, appropriate, well-developed, and quantifiable with regard to specific goals and accomplishments?

Is the time frame for the assessments appropriate to evaluate the trial progress?

Study Timeline

Specific to applications involving clinical trials

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 three points: (1) a complete description of all proposed procedures including the species, strains, ages, sex, and total numbers of animals to be used; (2) justifications that the species is appropriate for the proposed research and why the research goals cannot be accomplished using an alternative non-animal model; and (3) interventions including analgesia, anesthesia, sedation, palliative care, and humane endpoints that will be used to limit any unavoidable discomfort, distress, pain and injury in the conduct of scientifically valuable research. Methods of euthanasia and justification for selected methods, if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals, is also required but is found in a separate section of the application. For additional information on review of the Vertebrate Animals Section, please refer to the Worksheet for Review of the Vertebrate Animals 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.

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

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 Resource Sharing Plan(s) (i.e., Sharing Model Organisms) or the rationale for not sharing the resources, is reasonable.

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 NCCIH, 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.

  Appeals of initial peer review will not be accepted for applications submitted in response to this NOFO.

Applications will be assigned to NINDS. Applications will compete for available funds with all other recommended applications submitted in response to this NOFO. Following initial peer review, recommended applications will receive a second level of review by the National Advisory Neurological Disorders and Stroke (NANDSC) Council. The following will be considered in making funding decisions:

• 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.

As part of the scientific peer review, all applications will receive a written critique.

Applications 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.

Appeals of initial peer review will not be accepted for applications submitted in response to this NOFO.

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this NOFO. Following initial peer review, recommended applications will receive a second level of review by the National Advisory Neurological Disorders and Stroke (NANDSC) Council. The following will be considered in making funding decisions:

• 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

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement Section 2.4.4 Disposition of Applications.

Section VI. Award Administration Information

1. Award Notices

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement. This request is not a Notice of Award nor should it be construed to be an indicator of possible funding.

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 recipient's business official.

Recipients must comply with any funding restrictions described in Section IV.6. 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 NOFO 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 and results reporting of all trials whether required under the law or not. For more information, see https://grants.nih.gov/policy/clinical-trials/reporting/index.htm

Institutional Review Board or Independent Ethics Committee Approval: Recipient institutions must ensure that all protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the recipient 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).

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

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Recipients, and Activities, including of note, but not limited to:

• Federal-wide Standard Terms and Conditions for Research Grants
• Prohibition on Certain Telecommunications and Video Surveillance Services or Equipment
• Acknowledgment of Federal Funding

If a recipient is successful and receives a Notice of Award, in accepting the award, the recipient agrees that any activities under the award are subject to all provisions currently in effect or implemented during the period of the award, other Department regulations and policies in effect at the time of the award, and applicable statutory provisions.

If a recipient receives an award, the recipient must follow all applicable nondiscrimination laws. The recipient agrees to this when registering in SAM.gov. The recipient must also submit an Assurance of Compliance (HHS-690). To learn more, see the Laws and Regulations Enforced by the HHS Office for Civil Rights website. 

HHS recognizes that NIH 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. 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 NOFO.

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 System for Award Management (SAM.gov) requirements. SAM.gov requires Federal agencies to review and consider information about an applicant in the designated integrity and performance system (currently SAM.gov) prior to making an award. An applicant can review and comment on any information in the responsibility/qualification records available in SAM.gov. NIH will consider any comments by the applicant, in addition to the information available in the responsibility/qualification records in SAM.gov, 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 2 CFR Part 200.206 “Federal awarding agency review of risk posed by applicants.” This provision will apply to all NIH grants and cooperative agreements except fellowships.

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (HHS) grant administration regulations at 2 CFR Part 200, and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the recipients is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the recipients for the project as a whole, although specific tasks and activities may be shared among the recipients and NIH as defined below.

The PD(s)/PI(s) will have the primary responsibility for: 

• Overseeing the overall budget, activities, and performance of the Project. The institution should obtain appropriate prior approval for any change in PI effort.
• Accepting the participatory and cooperative nature of the collaborative research process and complying with policies and practices developed by the NIH Pragmatic Trials Collaboratory governing structure.
• Sharing data, resources, and software according to the Data Management and Sharing Plan for the NIH HEAL Initiative Public Access and Data Sharing requirements (https://heal.nih.gov/about/public-access-data).
• Participating in all meetings of the NIH Pragmatic Trials Collaboratory Steering Committee. Identifying study team members with relevant expertise to participate in program-wide Work Groups and sub-committees (as appropriate).
• Cooperating with the NIH Pragmatic Trials Collaboratory Steering Committee, CC, research partners, and NIH staff in the design and conduct of protocols, analysis of data, and reporting of results of research.
• Agreeing to accept close coordination, cooperation, and management of the project with NIH, including those outlined below under "NIH Responsibilities."
• Submitting materials to the NIH Program Director, Coordinating Center, and/or Steering Committee as requested. This will include regular reports of accomplishments and roadblocks, conference and meeting summaries, and other reports as requested.
• Materials submitted will meet all subject and formatting requirements.
• Recipients will submit a detailed transition request for the UH3 Project trial conduct phase, outlining UG3 progress, how negotiated UG3 Milestones have been met, as well as detailed plans, budget and annual milestones for the UH3 trial conduct phase. Note that, funding of the UG3 project planning phase cooperative agreement does not guarantee support of the UH3 Project trial conduct phase.
• Any of the above function may be performed by the applicant organization or by subcontract to the applicant organization.
• Recipients will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies.

NIH staff has substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

• The NIH Project Scientist will work with the PD(s)/PI(s) and the Steering Committee to ensure the objectives of the program are being met. The primary responsibility for the program resides with the recipient, although specific tasks and activities will be shared among the awardee and the NIH Project Scientist.
• NIH staff will interact with the PD(s)/PI(s) on a regular basis to monitor progress. Monitoring may include: regular communication with the PD(s)/PI(S) and his/her staff, periodic site visits for discussion with the recipients’ research team, observation of field data collection and management techniques, fiscal reviews, and other relevant stewardship activities.
• The NIH reserves the right to terminate or curtail the award (or an individual component of the award) in the event of inadequate progress or data reporting.
• Additional NIH staff may participate in all Work Groups, implementation teams and committees, including the Steering Committee, as appropriate. NIH may designate staff from other federal agencies to participate, if advantageous to facilitate the activities of the program.
• NIH staff will act as a resource and facilitator for activities of the with non-NIH HCS researchers and other NIH, DHHS, or other federally-sponsored research networks that may be relevant to this effort.
• NIH staff will provide input, expert advice, and suggestions in the design, development, and coordination of the infrastructure development and implementation efforts.
• NIH staff will report periodically on progress of the program to the NIH Common Fund Executive Committee and interested IC Directors.
• NIH staff will conduct an administrative review of the UH3 transition request to determine whether the Project will transition to UH3 funding and be implemented. Criteria for transition to the UH3 phase used in the NIH administrative review include: successful achievement of the UG3 milestones, potential for successfully meeting the UH3 trial conduct phase plans and milestones, demonstrated ability of the team to work within the consortium arrangement, and the availability of funds.
• Additionally, an agency program official or IC program director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.

Areas of Joint Responsibility include:

• Ensuring that NIH HCS sites and investigators as well as NIH and other research partners fully comply with federal regulatory requirements. This includes but is not limited to those relating to human subjects’ protections, informed consent, and reporting of adverse events.
• Jointly developing appropriate confidentiality procedures for data collection, processing, storage and analysis to ensure the confidentiality of data on individual health care provider organization patients, health care providers and other institutions involved in any Collaboratory research projects.
• Participating in the NIH Pragmatic Trials Collaboratory Steering Committee to address issues that span all projects, provide input into the policies and processes of the NIH Pragmatic Trials Collaboratory, and assist in dissemination of policies and processes that enable research in partnership with health care systems, their patients, and practitioners. At a minimum, the Steering Committee will be composed of one representative from each of the Projects, one representative from each Work Group, one representative from the CC, the NIH Program Coordinator, and representatives from various NIH ICs. The combined vote of NIH membership may never exceed 1/3 of the total committee membership.
• Participating in the NIH Pragmatic Trials Collaboratory Work Groups that have been established as the core collaborative activity of this program. The Work Groups provide a forum for discussion of challenges and solutions across projects; harmonized and standardized policies and processes will be vetted in these groups. Work Groups have been established in the following areas: Electronic Health Records, Regulatory /Ethics, Biostatistics & Study Design, Health Provider-Systems Interactions, Stakeholder Engagement, Phenotype & Data Standards, Health Equity, Implementation Science, and Patient Reported Outcomes (http://www.rethinkingclinicaltrials.org/cores-and-working-groups/). Additional Work Groups may be identified as the NIH Pragmatic Trials Collaboratory expands with new projects. Work Groups are open to participation by individuals from all funded Projects, the CC, and the NIH.
• Recipients will work with other Collaboratory investigators and NIH to identify common clinical outcome measures (such as measures of quality of life, physical function, pain or fatigue). NIH and CC staff will work with the Principal Investigators to facilitate this aspect of Projects.
• Establishing and adherence by each Project Team (Project recipient , CC recipient , and NIH staff) to a written plan of engagement, with timelines, to ensure timely delivery of the tested implementation plan.
• Working together with the CC through all phases of the projects, including the trial conduct and close out, to assure all resources, materials, protocols, data, best practices, program policies, and lessons learned, as well as software or sets of code, are disseminated broadly through the CC, to inform researchers and health care systems engaged in research in health care settings.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between recipients and NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual recipient. This special dispute resolution procedure does not alter the recipient's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and HHS regulation 45 CFR Part 16.

3. Data Management and Sharing

Consistent with the 2023 NIH Policy for Data Management and Sharing, when data management and sharing is applicable to the award, recipients will be required to adhere to the Data Management and Sharing requirements as outlined in the NIH Grants Policy Statement. Upon the approval of a Data Management and Sharing Plan, it is required for recipients to implement the plan as described.

Consistent with the NIH Policy for Data Management and Sharing, when data management and sharing is applicable to the award, recipients will be required to adhere to the Data Management and Sharing requirements as outlined in the NIH Grants Policy Statement. Upon the approval of a Data Management and Sharing Plan, it is required for recipients to implement the plan as described. 

HEAL Data Sharing Requirements 

NIH intends to maximize the impact of HEAL Initiative-supported projects through broad and rapid data sharing.  All HEAL Initiative award recipients, regardless of the amount of direct costs requested for any one year, are required to comply with the HEAL Public Access and Data Sharing Policy. HEAL award recipients must following all requirements and timelines developed through the HEAL Initiative Data Ecosystem (https://heal.nih.gov/about/heal-data-ecosystem), as described in HEAL’s compliance guidance (See “Already Funded” section: https://heal.nih.gov/data/complying-heal-data-sharing-policy):  
  

1. Select a HEAL – Compliant data repository (https://www.healdatafair.org/resources/guidance/selection)   

Data generated by HEAL Initiative-funded projects must be submitted to study-appropriate, HEAL-compliant, data repositories to ensure the data is accessible via the HEAL Initiative Data Ecosystem. 

Some repositories require use of specific data dictionaries or structured data elements, so knowing your repository’s requirements up front can help reduce the burden of preparing data for submission. 

HEAL-funded recipients  must follow requirements for selected repository  

2. Within one year of award, register your study with the HEAL platform (https://heal.github.io/platform-documentation/study-registration/)  

This process will connect the Platform to information about your study and data, including metadata, and identify the selected repository. HEAL requests initial submission within one year of award, with annual updates, and to be updated in accordance with any release of study data. 

3. Within one year of award, submit HEAL-specific study-level metadata.  

Some of the required study-level metadata (https://github.com/HEAL/heal-metadata-schemas/blob/main/for-investigators-how-to/study-level-metadata-fields/study-metadata-schema-for-humans.pdf) will be auto-populated as part of the registration process. 
  

4. Submit data and metadata (and code, if applicable) to HEAL-Compliant repository   

At the completion of the study and/or when prepared to make the final data deposits in the repositor(ies) of choice, ensure your study registration (https://heal.github.io/platform-documentation/study-registration/) is complete. 

Submit data dictionaries to the HEAL data ecosystem, if applicable. 

The NIH HEAL Initiative expects data sharing timelines to align with timeline requirements stated in the Final NIH Policy for Data Management and Sharing (NOT-OD-21-013). 

6. Additional Requirements for HEAL Initiative studies conducting clinical research or research involving human subjects. 

These studies must meet the following additional requirements:  

HEAL Initiative trials that are required to register in clinicaltrials.gov should reference support from and inclusion in the HEAL Initiative by including the standardized terms “the HEAL Initiative (https://heal.nih.gov/)” in the Study Description Section. 

All new HEAL clinical pain studies are required to use core questionnaires required by the HEAL Clinical Data Elements (CDE) Program (https://heal.nih.gov/data/common-data-elements). Outside of the core questionnaires, studies should select questionnaires from among the repository of supplemental questionnaires that are already being used by other HEAL clinical pain studies. The program has created the CDE files containing standardized variable names, responses, coding, and other information for all of these questionnaires The program has also formatted the case-report forms in a standardized way that is compliant with accessibility standards under Section 508 of the Rehabilitation Act of 1973 (29 U.S.C § 794 (d); https://www.govinfo.gov/content/pkg/USCODE-2011-title29/html/USCODE-2011-title29-chap16-subchapV-sec794d.htm) which “require[s] Federal agencies to make their electronic and information technology accessible to people with disabilities.”  

Studies that wish to use questionnaires not already included in the HEAL CDE repository should consult with their program official and the HEAL CDE team. New questionnaires will be considered for inclusion in the repository on a case-by-case basis and only when appropriate justification is provided.   

HEAL Initiative clinical studies that are using copyrighted questionnaires  are required to obtain licenses for use prior to initiating data collection. Licenses must be shared with the HEAL CDE team and the program officer prior to use of copyrighted materials. For additional information, visit the HEAL CDE Program (https://heal.nih.gov/data/common-data-elements).  

To the extent possible, all other (non-pain) HEAL studies conducting clinical trials or research involving human subject are expected to use questionnaires by the HEAL Clinical Data Elements (CDE) Program (https://heal.nih.gov/data/common-data-elements) if applicable and relevant to their research.  

To the extent possible, HEAL recipients  are expected to integrate broad data sharing consent language into their informed consent forms. 

Additional details, resources, and tools to assist with data related activities can be found at https://www.healdatafair.org/. Budgeting guidance for data sharing can be found in NOT-OD-21-015 and the NIH Scientific Data Sharing site. 

All data collected as part of the NIH HEAL Initiative are so collected under a Certificate of Confidentiality and entitled to the protections thereof. Institutions who receive Data and/or Materials from this award for performance of activities under this award are required to use the Data and/or Materials only as outlined by the NIH HEAL Initiative, in a manner that is consistent with applicable state and federal laws and regulations, including any informed consent requirements and the terms of the institution’s NIH funding, including NOT-OD-17-109 and 42 U.S.C. 241(d). Failure to adhere to this criterion may result in enforcement actions. 

4. Reporting

When multiple years are involved, recipients will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement. NIH NOFOs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 2 CFR Part 200.301.

The Federal Funding Accountability and Transparency Act of 2006 as amended (FFATA), includes a requirement for recipients of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later.  All recipients 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 2 CFR Part 200.113 and Appendix XII to 2 CFR Part 200, 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 (Responsibility/Qualification in SAM.gov, formerly 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 2 CFR Part 200 – Award Term and Conditions for Recipient Integrity and Performance Matters.

Section VII. Agency Contacts

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten submission by the due date, and post-submission issues)

Finding Help Online: https://www.era.nih.gov/need-help (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: 301-637-3015

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

Linda Porter, PhD
National Institute for Neurological Disorders and Stroke (NINDS)
Telephone: 301-451-4460
Email: porterl@ninds.nih.gov

Marlene Peters Lawrence, MAS, BSN, RN
National Institute for Neurological Disorders and Stroke (NINDS)
Telephone: 301-480-9636
Email:   marlene.peterslawrence@nih.gov

Helena H. Ahn, PhD
Eunice Kennedy Shriver National Institute of Child Health and Human Development
Telephone: 301-827-3207
Email: helena.ahn@nih.gov 
 

Charles H Washabaugh, PhD
NIAMS - NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
Phone: 301-496-9568
E-mail: washabac@mail.nih.gov

Wendy Weber, N.D., Ph.D., M.P.H.
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-402-1272
Email: weberwj@mail.nih.gov

Dena Fischer, DDS, MSD, MS
NIDCR - NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH
Phone: (301) 594-4876
E-mail: dena.fischer@nih.gov

Alexis Bakos, Ph.D., M.P.H., R.N.
NATIONAL INSTITUTE ON AGING (NIA)
Phone: 240-276-6609
E-mail: alexis.bakos@nih.gov

Jessica M. McKlveen, Ph.D.
Director, Office of Scientific Review
Division of Extramural Activities
National Center for Complementary & Integrative Health (NCCIH) 
Email: jessica.mcklveen@nih.gov

Chief Grants Management Officer
National Institute of Neurological Disorders and Stroke (NINDS)
Email: ChiefGrantsManagementOfficer@ninds.nih.gov  

Margaret Young
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-642-4552
Email: margaret.young@nih.gov

Erik Edgerton
NIAMS - NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
Phone: 301-594-7760
E-mail: erik.edgerton@nih.gov

Debbie Chen
National Center for Complementary and Integrative Health (NCCIH)
Phone: 301-594-3788
Email: debbie.chen@nih.gov

Gabriel Hidalgo, MBA
NIDCR - NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH
Phone: 301-827-4630
E-mail: hidalgoge@mail.nih.gov

Kathleen Moy
NATIONAL INSTITUTE ON AGING (NIA)
Phone: 301.827.2856
E-mail: kathleen.moy@nih.gov

Section VIII. Other Information

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 2 CFR Part 200.