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.

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

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

Part 2. Full Text of Announcement

Section I. Notice of Funding Opportunity Description

Purpose

The purpose of this Notice of Funding Opportunity (NOFO) is to advance the understanding, assessment, measurement, treatment, and prevention of pain in infants, children, and adolescents, including those with disabilities and/or experiencing health disparities. This NOFO is part of the NIH Helping to End Addiction Long-Term (HEAL) Initiative, a trans-agency effort to fund research to find scientific solutions to the national opioid public health crisis (see below for additional HEAL details). As part of this initiative, the HEAL KIDS (Knowledge, Innovation and Discovery Studies) Pain program is comprised of interrelated programs addressing critical areas of pediatric pain research. The interrelated programs will be funded under separate NOFOs.

This NOFO, the HEAL KIDS Pain: Acute Pain Clinical Trials (APCT) program, supports research with high priority primary outcomes focused on improving the assessment, management, and/or treatment of acute pain in pediatric patients through innovative, multi-site clinical trials, while integrating relevant behavioral and social influences and contexts on pain experience as high priority secondary outcomes. Behavioral and social influences may include, but are not limited to, inclusion of social determinants of health, social and environmental barriers, and other influences on the incidence of pain, the impact of perception and experiences of pain, and the influences on pain reporting and opioid pain management. The impact of acute pain on families and caregivers and how family and caregiver dynamics impact pain experiences and reporting is of interest. Advancing health equity and mitigating health disparities in acute pain management are also high priority secondary outcomes. Clinical trials focused solely on testing the effects of a behavioral intervention on pain outcomes will not be considered high priority projects. However, trials that include behavioral interventions as standard care and trials that include behavioral interventions studied in conjunction with other pharmacologic or physical interventions may be of interest.

Background

Pain in infants, children, and adolescents is common, often under-recognized, inconsistently assessed and inadequately measured and treated. Compared with adult patients, pediatric patients are less likely to receive adequate analgesia in the medical setting. Moreover, the relationship between pain and human development, including any potential effects of repeated pain experiences on future physical dependency, remains largely unexplored.

Both the Center for Disease Control (CDC) and the National Academy of Medicine define acute pain as a physiologic response to noxious stimuli that can become pathologic and is of sudden onset and time limited (defined as having a duration of less than 1 month). It is usually clearly linked to a specific event, injury, illness, or intervention. The CDC further states that "unresolved acute pain or subacute pain (defined as pain that has been present for 1 to 3 months) can evolve into chronic pain." This definition of acute pain comes from the CDC Clinical Practice Guideline for Prescribing Opioids for Pain - United States, 2022. However, this guideline only provides opioid prescribing recommendations for outpatients 18 years of age or older. Few guidelines related to acute pain in pediatric populations exist, mainly due to a lack of rigorous generalizable data to inform evidence-based practice guidelines, especially in pre-verbal, non-verbal, and unconscious/unresponsive pediatric patients. To date, most pediatric pain clinical trials have had small sample sizes, lack control groups and/or unblinded raters, and utilize convenience sampling which may not provide the most robust data for safety and efficacy of treatments. Well-designed clinical trials are needed to inform future clinical practice guidelines.

A number of factors contribute to the lack of clinical guidelines related to acute pain in pediatric populations. Clinically useful assessment tools that are precise, reliable, validated, ethnically and culturally appropriate, accessible, and effective across a wide range of pediatric populations and the continuum of care are limited. Current, updated methods of assessing acute pain in pre-verbal, non-verbal, unconscious/unresponsive pediatric patients, including those with intellectual disabilities, remain insufficient and are frequently based on physiologic measurements that may be influenced by a variety of factors. The long-term neurobiological outcomes and negative sequelae of acute pain on the developing brain, from birth through adolescence, remain grossly understudied. Conversely, the same long-term outcomes and negative sequelae of opioid use in the medical management of acute pain on the developing brain have also been understudied. Data to support evidence-based management of acute pain in pediatric patients due to painful conditions or disease, invasive treatment modalities, or recurrent painful exposures and/or procedures, as well as the increased risk for the development of physiologic dependency on opioids related to inadequate pain management is substantially lacking. Identifying factors that are predictive of treatment effectiveness in well-defined pediatric patient populations are needed. Evidence-based opioid weaning protocols and appropriate pharmacological methods for treating physiologic opioid dependency in pediatric patients have not been well-established and are needed to mitigate the need for long-term opioid use. Multimodal analgesic approaches are currently recommended to address acute pain in hospitalized pediatric patients; however, rigorous generalizable scientific data to support these multimodal pharmacological approaches for acute pain management in pediatric patients are not well established. Finally, studies have shown disparities exist in acute pain management in pediatric patients related to race, ethnicity, and sex or gender. Research is needed to ensure management and treatment of acute pain is both ethical and equitable for all pediatric populations regardless of race, ethnicity, sex or gender, socioeconomic level, intellectual and physical disabilities, access to healthcare, and/or proficiency with the English language.

Research Objectives and Scope

The overall goal of the APCT program is to support multi-site clinical trials that seek to establish or implement systematic and/or multimodal approaches for the diagnosis, assessment, and effective treatment of acute pain, including acute flares of chronic pain, for pediatric patients across the continuum of care (including pre-hospital settings, outpatient clinic or urgent care, emergency departments, neonatal and pediatric intensive care units, dental care settings and acute care/hospital facilities). Innovative, groundbreaking, large-scale, multi-site clinical trials with primary outcomes focused on improving the assessment, management, and/or treatment of acute pain in pediatric patients are considered high program priority. Research testing behavioral interventions to manage pain as the primary outcome will not be considered as high priority since several currently funded HEAL trials are testing behavioral interventions for pain management. Investigators wishing to test the effectiveness of behavioral interventions should contact program officials from individual Institutes (ICs) and Centers to find an appropriate NOFO. Research testing software or decision-making tools that help providers and patients determine the most effective and safe methods for pharmacological or device pain management are allowed.

This NOFO uses a U01 cooperative agreement mechanism. The U01 mechanism is a Research Project Cooperative Agreement that supports discrete, circumscribed projects to be performed by investigator(s) in an area representing specific interests and competencies. It is used when substantial programmatic involvement is anticipated between the awarding Institute and Center. A multi-site clinical trial involves the implementation of the same clinical protocol at two or more investigational sites that are typically administratively or corporately distinct from one another.

Proposed acute pain clinical trials may include the entire age spectrum of pediatric patients with acute pain and may include randomized controlled efficacy, effectiveness, or pragmatic designs and include patient and/or parent-reported outcomes using validated measures. Applications that propose pharmacological studies to address the limited evidence for the dosing and efficacy of different classes of analgesics to manage acute pain in pediatric patients, as well as dissemination and implementation research clinical trials that could inform acute pain treatment consensus guidelines through the continuum of care are also considered within scope. Applicants are expected to ensure pediatric populations from health disparity populations (i.e. NIH-designated populations) are represented in the proposed research.

Design examples include, but are not limited to:

• Clinical trials of the entire age spectrum of pediatric patients with acute pain in the pre-hospital, in-hospital, post-hospital discharge, and relevant outpatient settings (e.g., outpatient and ambulatory care clinics and surgical centers)
• Utilizing innovative pragmatic trial designs (e.g., effectiveness trials, stepped-wedge designs, etc.) as well as randomized controlled trials and patient and/or parent-reported outcomes using validated measures.
• Studies on acute pain assessment and treatments that cross through the continuum of care settings (pre-hospital, Emergency Department (ED), Pediatric Intensive Care Unit (PICU), Neonatal Intensive Care Unit (NICU)*, inpatient, outpatient, acute rehabilitation, dental care settings) and include a primary or secondary focus on health equity and social determinants of health.
• Conducting pharmacological studies to address the limited evidence for the dosing, safety, and efficacy of different classes of analgesics to manage acute pain in pediatric patients.
• Developing evidence-based opioid weaning protocols and appropriate pharmacological methods for treating physiologic opioid dependency in pediatric patients exposed to opioids as part of their medical management.
• Effective methods to manage/treat acute menstrual pain, vulvar pain, pelvic pain, and other gynecologic pain and long-term outcomes and negative sequelae of acute gynecologic pain in female adolescents.
• Dissemination and implementation clinical trials related to development of future acute pain treatment consensus guidelines through the continuum of care (pre-hospital, ED, PICU, NICU, inpatient, outpatient, acute rehabilitation, dental care settings).
• NOTE: * Although neonates or infants being assessed and treated for Neonatal Abstinence Syndrome (NAS) or Neonatal Opioid Withdrawal (NOW) related to maternal opioid use may be NICU patients, this population is excluded from study under this NOFO as previously funded HEAL initiatives have addressed this specific patient population.

Additional examples of meaningful high priority secondary outcomes that would be responsive to this NOFO include, but are not limited to:

• Generation of data to support evidence-based management (pharmacological, nonpharmacological, or multicomponent) of acute pain in pediatric patients across the continuum of care
• Addressing challenges in assessing acute pain in pre-verbal, non-verbal, unconscious/unresponsive pediatric patients, including those with intellectual disabilities
• Outcomes and negative sequelae of acute pain on the developing brain, from birth through adolescence, as well as outcomes and negative sequelae of opioid use in the medical management of acute pain on the developing brain.
• Research to ensure management and treatment of acute pain is both ethical and equitable for all pediatric populations regardless of race, ethnicity, sex or gender, socioeconomic level, intellectual and physical disabilities, access to healthcare, and/or proficiency with the English language
• Generation of generalizable scientific data to support multimodal approaches for acute pain management in the pediatric patient population (e.g., multimodal analgesia is the current pharmacologic approach despite lack of scientific foundation)

Clinical Trials focused solely on testing the effects of a behavioral intervention on pain outcomes will not be considered high priority projects. However, trials that include behavioral interventions as standard of care and trials that include behavioral interventions studied in conjunction with other pharmacologic or physical interventions may be of interest.

Participating Institutes and Centers Specific Interests:

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) is to support research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases. In the context of this NOFO, NIAMS encourages trials to manage acute pain flares in children with chronic pain conditions, such as Osteogenesis imperfecta, and in other rheumatological, orthopedic, dermatological, bone and cartilage, and inflammatory muscle diseases.

National Institute of Neurological Disorders and Stroke (NINDS)

The NINDS supports research seeking fundamental knowledge about the nervous system and its disorders to improve the neurological health of all people. In the context of this NOFO, the NINDS encourages clinical trials focused on the management of acute pain in children who experience neuropathic pain including headache, complex regional pain syndrome, pain after spinal cord or other traumatic injury, and acute pain exacerbations in children with genetic or autoimmune causes of neuropathic pain. NINDS also encourages research focused on the assessment and management of pain in children with neurologic disorders that may limit their ability to communicate their pain experiences and needs. NINDS values community-engaged research and encourages investigators to engage with community partners and incorporate feedback from persons with lived experience across multiple stages of their proposed project. NINDS, as part of NIH, strives for rigor and transparency in all research it supports. Proposed clinical trial should be 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. The proposed trial design should likewise demonstrate a rigorous and transparent approach.

National Institute of Nursing Research (NINR)

The National Institute of Nursing Research (NINR) supports research to solve pressing health challenges and inform practice and policy - optimizing health and advancing health equity into the future. NINR discovers solutions to health challenges through the lenses of health equity, social determinants of health, population and community health, prevention and health promotion, and systems and models of care. NINR welcomes applications whose study aims address social determinants of pediatric acute pain recognition, assessment, and management, and those that address structural/systemic roots of disparities in pediatric acute pain care.

Organizational Structure

Applications submitted in response to this NOFO are expected to propose an organizational structure and leadership plan to allow for successful completion of the proposed clinical trial. The clinical trial program will require integration and management of various stakeholders involved in clinical research including but limited to clinical trialists, study coordinators, data management expertise, statistical expertise, and clinical site management. Applicants must propose a Steering Committee plan in accordance with the Cooperative Agreement requirements.

Executive Committee

The Executive Committee (EC) will create a document of guidance in overall project planning and project management for all of the clinical trials supported via the U01 mechanism, including: prioritization of activities; determining and reviewing study feasibility.

A representative from Each awardee in the HEAL Kids Pain Initiative will participate in an executive committee that will be established at the time of award. The representation for the EC include:

• PI and/or Co-PI from each of the clinical trials awarded as U01 awards
• PI and/or Co-PI from the related DCCs for the clinical trials
• PI and/or Co-PI for the U24 Resource and Data Center award
• Project Manager from the U24 RDC award
• NICHD Project Scientists for the U01 and U24 awards

Coordination of HEAL KIDS Program

The various clinical trials proposed under the U01 mechanism will have the Resource and Data Center (U24) as the centralized home for coordinating data related activities across the HEAL kids Pain research program. The RDC will be primarily responsible for coordinating and/or facilitating scientific workgroups, convening subject matter expert panels and providing general infrastructure to facilitate scientific collaboration between all HEAL KIDS Pain program awardees. In order to do this, the RDC will be responsible for the establishment and management of an Executive Committee of all participating clinical trial and DCC PDs/PIs to facilitate communication and decision-making for the HEAL KIDS Pain program. It is also anticipated that the RDC will support programs to encourage continued scientific discussion to address the current needs/gaps in pediatric pain research. Anticipate at least (one) 1 facilitated meeting of all interested parties in the first year of award, in addition to one (1) other smaller NIH requested meetings per year as needed, and at least quarterly executive meetings.

Data Coordinating Center

Each application submitted in response to this NOFO must propose an independent Data Coordinating Center (DCC) as part of the proposed clinical trial program. The functions of the DCC for the application may include, but are not limited to:

• Developing data forms, protocol tools, as well as other data management systems for study coordination, protocol development, data integrity, data quality assurance, and study safety reporting
• Providing biostatistical expertise in sample size calculations and other statistical advice and support
• Computer programming including developing electronic data capture and other protocol tools
• Performing data analyses for monitoring, regulatory submissions, and study publications
• Developing a Data and Safety Monitoring Plan that includes coordinating a Data and Safety Monitoring Board (DSMB), single IRB (sIRB) activities, and FDA Investigational New Drug (IND) or Investigational Device Exemption (IDE) management, if applicable
• Initiating and implementing all subcontracts for participating clinical sites for management of capitation funds, etc.
• Overall study coordination and quality assurance for the proposed clinical trials

A DSMB must be appointed to monitor the proposed clinical trial, according to NIH Institute-specific policies and in collaboration with the NIH Program Officer. As a part of its monitoring responsibility, the DSMB will submit recommendations regarding the continuation of each study in its purview and prepare a report for the PD(s)/PI(s) to provide to their Institutional Review Boards (IRBs).

Existing Networks with experienced clinical trial investigators and DCCs potentially positioned for this research are encouraged to apply. New Networks or multi-site collaborative research teams established in response to this solicitation will also be considered.

Resource Data Center (RDC)

Awardees will be supported in part by a centralized HEAL KIDS Pain Resource and Data Center (RDC) funded through a U24 mechanism (RFA-HD-24-012). The responsibilities of the RDC include, but are not limited to:

• Provide and manage a system to curate and harmonize clinical trial data collected via the awarded APCT U01 clinical trials and the HEAL KIDS Pain program. Examples of expected deliverables for the RDC include the development and/or recommendation of common data elements (CDEs); the development and/or recommendation of tools that facilitate the curation of data using relevant data standards; and the development of data formats, such as Study Data Tabulation Model (SDTM) file data formats, for the submission of clinical trial data to relevant HEAL data ecosystems for future use and analysis
• Provide administrative, logistical, and coordination communication for meetings, working groups, and other committees related to the HEAL KIDS Pain program and HEAL Initiative throughout the funding period of award(s).
• Oversee HEAL Data sharing through established NIH data repositories, study registration with the HEAL Data Platform, and other HEAL-related requirements for funded programs within the HEAL KIDS Pain program.

U01 awardees and their respective DCC investigators are expected to work collaboratively with the RDC. An executive committee (EC)will be formed upon award to determine prioritization of activities across the HEAL KIDS Pain Program. Applicants are expected to refer to the RDC U24 NOFO (RFA-HD-24-012) to determine the specific activities provided by the common RDC.

The NIH HEAL Initiative:

This NOFO is part of the NIH's Helping to End Addiction Long-Term (HEAL) initiative to speed scientific solutions to the national opioid public health crisis. The NIH HEAL Initiative bolsters research across NIH to (1) improve treatment for opioid misuse and addiction and (2) enhance pain management. More information about the HEAL Initiative is available at https://heal.nih.gov/.

Diversity

In addition to scientific diversity, applicants should strive to incorporate diversity in their team development plan. 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. NIH encourages institutions to diversify their student and faculty populations to enhance the participation of individuals from groups that are underrepresented in the biomedical, clinical, behavioral, and social sciences. Please refer to Notice of NIH's Interest in Diversity NOT-OD-20-031 ?for more details.

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.

PI Meeting Attendance

The NIH HEAL Initiative will require a high level of coordination and sharing between investigators. It is expected that NIH HEAL Initiative award recipients will cooperate and coordinate their activities after awards are made by participating in Program Director/Principal Investigator (PD/PI) meetings, including an annual NIH HEAL Investigators meeting, as well as other activities.

NIH requires that all projects funded under this RFA will actively coordinate, collaborate, and share data with the other HEAL KIDS Pain program grantees, as allowed and appropriate.

Awardees will be expected to interact with other awardees of the HEAL KIDS Pain Initiative via NIH-sponsored workshops and meetings. Awardee project teams are expected to work interactively, sharing data, protocols, and tools within the HEAL KIDS Pain initiative and NIH HEAL Data Ecosystem and, as rapidly as possible, with the broader scientific community.

Clinical trial and DCC PDs/PIs will be expected to participate, as required, with the RDC on the HEAL KIDS Pain Executive Committee to facilitate communication and decision-making for the HEAL KIDS Pain program.

HEAL funded researchers must make their HEAL data Findable, Accessible, Interoperable, and Reusable (FAIR) in line with the?HEAL Data Sharing Policy?and the broader efforts across NIH, as outlined in the?NIH Strategic Plan for Data Science. The RDC will support investigators in meeting the following HEAL Data Sharing Policy requirements:

• Select a HEAL compliant repository for long-term data storage.
• Register your HEAL study in the HEAL Data Platform.
• Submit metadata to the HEAL Data Platform.
• Pain clinical studies must use HEAL core Common Data Elements (CDEs).
• To the extent possible, HEAL awardees should use broad consent language.

Pre-Application Technical Assistance Information

An informational pre-application technical assistance webinar, addressing the scientific and administrative issues associated with this initiative, is anticipated. The purpose of this webinar will be to (1) familiarize potential applicants with established NIH guidelines and criteria for review, (2) discuss the areas of programmatic emphasis, and (3) facilitate the submission of a well-organized application.

Applicants interested in the pre-application technical assistance webinar should contact Tammy Jenkins ([email protected]) or Perdita Taylor-Zapata ([email protected]) to request further details. Participation in the webinar is not required to submit an application in response to this NOFO. Individual consultation, separate from the pre-application webinar, is also available upon request and encouraged for all interested applicants.

Applications that are incomplete or Not Responsive to this NOFO:

Examples of applications that include the following will be considered non-responsive to this NOFO and will be withdrawn from consideration:

• Animal or in vitro studies
• Single site clinical trials
• Primarily mechanistic studies or mechanistic clinical trials where the primary focus of the research is on, for example, natural history or physiological basis of disease rather than interventions. Mechanistic components within a clinical trial may be acceptable and should be discussed with the Scientific Contact(s), as needed.
• Multi-site trials that do not include/propose a site to function as a Data Coordinating Center
• Clinical trials focused on neonates/infants exposed to opioids through maternal transmission, including Neonatal Abstinence Syndrome or Neonatal Opioid Withdrawal and their sequelae

Please Note: Although efficacy clinical trials are included under the scope of this NOFO, Phase 2 clinical trials may be better suited for another HEAL program, the Early Phase Pain Investigation Clinical Network (EPPIC-Net). EPPIC-Net is a HEAL-funded clinical trials network designed to conduct phase 2 trials of new or repurposed assets for the treatment of pain across the lifespan. For more information about EPPIC-Net please see: https://heal.nih.gov/research/clinical-research/eppic-net.

Plan for Enhancing Diverse Perspectives (PEDP)

• This NOFO requires a Plan for Enhancing Diverse Perspectives (PEDP) as described in NOT-MH-21-310, submitted as Other Project Information as an attachment (see Section IV).
• Applicants are strongly encouraged to read the NOFO instructions carefully and view the available PEDP guidance material. The PEDP will be assessed as part of the scientific and technical peer review evaluation, as well as considered among programmatic matters with respect to funding decisions.

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

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 Governments

• 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 Institutions) 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 SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• 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 registrations; 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 SF424 (R&R) Application Guide.

Minimum Requirements for the PD(s)/PI(s):

• The PD(s)/PI(s) and other key personnel must have prior experience in conducting multi-site clinical studies/trials in the previous five years. Experience in planning, developing and executing pediatric studies, and the special consent and IRB procedures needed for the conduct of research in pediatric patients and their families is strongly preferred
• The PD(s)/PI(s) must have the ability to assist the DCC in designing protocols, data collection systems, including distributed data entry, and capabilities and experience with research performance and data quality control systems
• The PD(s)/PI(s) should have the ability to hold subcontracts and distribute capitation funds to the clinical sites in a multi-site trial, and to maintain accounting for such funds with regular reporting to the NIH Program Official and Grants Management Specialist

2. Cost Sharing

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

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 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. Prior to submission: Applicants are strongly encouraged to consult with the IC or Center contacts for the area of science for which they are planning to develop an application. Early contact (at least 12 weeks prior to submission) is encouraged. This early contact will provide an opportunity to discuss and clarify NIH policies and guidelines, including the scope of the project relative to the HEAL Initiative mission and intent of this NOFO.

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:

Tammara Jenkins, MSN, RN, PCNS-BC
Telephone: 301-435-6837
Email: [email protected]

Page Limitations

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this NOFO.

SF424(R&R) Cover

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

SF424(R&R) Project/Performance Site Locations

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

SF424(R&R) Other Project Information

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

Facilities and Other Resources: Describe how the available infrastructure and performance site(s) will be leveraged to facilitate the efficient operation of the proposed multi-site clinical trial. Address the appropriateness of the environment including the infrastructure for the trial, access to the appropriate patient population, and engagement of providers, hospital(s), hospital unit(s), health system(s), and/or other care settings.

Other Attachments: The application must include the following documents, uploaded as separate pdf files with the names indicated below.

1. Clinical Research Capabilities

The filename "Clinical Research Capabilities.pdf" should be used and will be reflected in the final image bookmarking for easy access for reviewers.

Describe the resources available to conduct clinical trials and studies and provide a table or other appropriate format that demonstrates the site's prior experience with pediatric clinical research. List all trials and studies conducted at the site over the past 3 years. The information should include:

A: name of the study/trial

B: a brief description of the study/trial

C: funding source(s) (NIH, industry, foundation, other)

D: sex/gender, race, and ethnicity of participants enrolled using standard NIH inclusion categories within pediatrics

E: planned total enrollment for the site

F: actual total enrollment at the site

2. Data Coordinating Center (DCC) Capabilities

The filename "DCC Capabilities.pdf" should be used and will be reflected in the final image bookmarking for easy access for reviewers.

Describe the resources available to function as the DCC for the proposed clinical trial. Applicants must include:

• Evidence of successful past performance as a DCC for a large-scale multi-site clinical trial, preferably in pediatrics
• Academic productivity as a DCC
• DCC staffing plan and capabilities
• Capacity and ability to manage data and communications
• Evidence of reporting capabilities
• Ability to provide on-site and off-site monitoring
• Technology transfer, data management, and protocol training capabilities
• Evidence of DCC administrative and management capabilities
• Intent to participate in a cooperative manner with the NIH HEAL initiative and HEAL KIDS Pain partners

3. Population Available for Clinical Trial

The filename "Available Populations.pdf" should be used and will be reflected in the final image bookmarking for easy access for reviewers.

Demonstrate patient populations available for enrollment in the proposed multi-site clinical trial and provide a table that describes the populations/admissions available at each clinical site, including ages, sex/gender, race, and ethnicity of the populations available for enrollment. Applicants must indicate if there are ongoing or pending clinical studies/trials that will limit availability of patients for the proposed trial.

4. HEAL Public Access and Data Sharing Policy

NIH intends to maximize the impact of HEAL Initiative-supported projects through broad and rapid data sharing and immediate access to publications (https://heal.nih.gov/about/public-access-data). Guidelines for complying with the HEAL Public Access and Data Sharing Policy can be found at https://heal.nih.gov/data/complying-heal-data-sharing-policy. Resources and tools to assist with data related activities can be found at https://www.healdatafair.org/. For more detail and specific data sharing requirements, see Section 4. Other plans.

Publications resulting from NIH HEAL Initiative funded studies must be immediately publicly available upon publication.

• For manuscripts published in journals that are not immediately open access, authors should arrange with journals in advance to pay for immediate open access.
• Costs to ensure manuscripts are immediately publicly available upon publication should be included in budget requests.

Prior to publication, HEAL expects investigators to alert their program officers of upcoming manuscripts to ensure coordination of communication and outreach efforts. Award recipients and their collaborators are required to acknowledge HEAL Initiative support by referencing in the acknowledgment sections of any relevant publication: This research was supported by the National Institutes of Health through the NIH HEAL Initiative (https://heal.nih.gov/) under award number [include specific grant/contract/award number; with NIH grant number(s) in this format: R01GM987654].

5. Biospecimen Plan

Processes required for orderly project closure including how the study will comply with the biorepository plans if specimens will be stored after the planned study testing and analyses are complete. If the clinical trial project includes biospecimen storage, discuss ownership of both data and biospecimens and a succession plan for ownership after federal support of the project.

6. Plan for Enhancing Diverse Perspectives (PEDP):

• In an "Other Attachment" entitled "Plan for Enhancing Diverse Perspectives," all applicants must include a summary of strategies to advance the scientific and technical merit of the proposed project through expanded inclusivity
• The PEDP should provide a holistic and integrated view of how enhancing diverse perspectives is viewed and supported throughout the application and can incorporate elements with relevance to any review criteria (significance, investigator(s), innovation, approach, and environment) as appropriate.
• Where possible, applicant(s) should align their description with these required elements within the research strategy section
• The PEDP will vary depending on the scientific aims, expertise required, the environment and performance site(s), as well as how the project aims are structured
• The PEDP may be no more than 1-page in length and should include a timeline and milestones for relevant components that will be considered as part of the review

Examples of items that advance inclusivity in research and may be part of the PEDP can include, but are not limited to:

• Discussion of engagement with different types of institutions and organizations (e.g., research-intensive, undergraduate-focused, minority-serving, community-based).
• Description of any planned partnerships that may enhance geographic and regional diversity.
• Plan to enhance recruiting of women and individuals from groups historically underrepresented in the biomedical, behavioral, and clinical research workforce.
• Proposed monitoring activities to identify and measure PEDP progress benchmarks.
• Plan to utilize the project infrastructure (i.e., research and structure) to support career-enhancing research opportunities for diverse junior, early- and mid-career researchers.
• Description of any training and/or mentoring opportunities available to encourage participation of students, postdoctoral researchers, and co-investigators from diverse backgrounds.
• Plan to develop transdisciplinary collaboration(s) that require unique expertise and/or solicit diverse perspectives to address research question(s).
• Publication plan that enumerates planned manuscripts and proposed lead authorship.
• Outreach and planned engagement activities to enhance recruitment of individuals from diverse groups as research participants including those from under-represented backgrounds.

For further information on the Plan for Enhancing Diverse Perspectives (PEDP), please see https://braininitiative.nih.gov/about/plan-enhancing-diverse-perspectives-pedp.

SF424(R&R) Senior/Key Person Profile

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

A multi-PI plan is encouraged. The PD(s)/PI(s) of the clinical trial must be experienced in the conduct of multi-center clinical trials including success in meeting milestones and timelines and have expertise in the content area of the proposed clinical trial. The experience of each PD/PI and all Key Personnel must be carefully documented, and roles and responsibilities must be well-defined. In addition, the responsibilities and authority of each PD/PI must be specified. The application must ensure that a multidisciplinary team of appropriate personnel (clinical trialist, clinician, Project Manager, study coordinator(s), etc.) are proposed at the contributing institutions to facilitate the implementation of all aspects of the clinical trial, including recruitment of subjects, design/implementation of the trial protocol, and coordination of roles/responsibilities of the clinical center(s) leadership. The application must include a description of the project management team and levels of effort and the governance structure for how the clinical sites and the DCC project management teams will integrate with one another.

All Key Personnel who are major scientific contributors to the study must provide an NIH Biosketch whether or not they are budgeted.

Steering Committee

Each applicant proposing a clinical trial will establish and maintain a Steering Committee (SC):

• This committee shall be comprised of at least three (3) members. Steering Committee membership may include experts and leaders in pediatrics care and research, clinical trialists, study coordinators, project managers, public health experts and/ or ethics experts. Representatives from the Government and Data Coordinating Center investigators will participate.
• The SC will create a document for guidance in determining study design and implementation; reviewing data analysis and discussing proposed approaches for publishing findings of studies conducted.

R&R or Modular Budget

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

The first year Base Budget will be limited to $2,100,000 in direct costs with allowances as follows:

• Subcontract awards for each clinical site in the multi-site trials, including Research Coordinator effort and other associated research-related costs
• Data Coordinating Center (DCC) activities.
• For any application proposing two or more subawards, a full-time Project Manager must be budgeted for coordination between sites, between the NIH and the lead site, and between the project team sites, DCC, and the RDC.
• Statistical staff
• Programming and analytic staff (including software expertise staff)
• Costs associated with data entry, management, collection, and analysis
• Data analysis, manuscript preparation
• Software licensing for HEAL KIDS Pain required data capture
• Arrangement of logistical services for protocol-specific costs, including subcontracts and supplies
• sIRB and DSMB associated costs
• Travel: The costs of travel to the NIH HEAL Annual Investigators' Meeting and up to 2 (two) NIH HEAL KIDS Pain-sponsored meetings over the award period
• Supplies and small equipment (itemized and justified)
• Other costs (itemized and justified)
• PEDP implementation costs, applicants may include allowable costs associated with PEDP implementation (as outlined in the Grants Policy Statement section 7: https://grants.nih.gov/grants/policy/nihgps/html5/section_7/7.1_general.htm).

The protocol budgets will consist of specific protocol-related allowances, capitated per subject enrolled in the trial. Either the applicant Clinical Site or the DCC should be designated as responsible for issuing protocol fund payments to the clinical sites involved in the clinical trial.

The awarded Clinical Site's facilities and administrative (F&A) rates on the initial competitive award will not be increased in future years due to changes in their negotiated rate agreements.

Total funding for clinical sites in the multi-site clinical trial depends on the base award to the applicant clinical site and reimbursements for approved protocol-related expenses. The overall provision of funds for the clinical trial protocol team is subject to the availability of NIH funding.

R&R Subaward Budget

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

The first year Base Budget will be limited to $2,100,000 in direct costs with allowances as follows:

• Subcontract awards for each clinical site in the multi-site trials, including Research Coordinator effort and other associated research-related costs
• Data Coordinating Center(DCC) activities:
• For any application proposing two or more subawards, a full-time Project Manager must be budgeted for coordination between sites, between the NIH and the lead site, and between the project team sites and DCC and the RDC.
• Statistical staff
• Programming and analytic staff (including software expertise staff)
• Costs associated with data entry, management, collection, and analysis
• Data analysis, manuscript preparation
• Software licensing for HEAL KIDS Pain required data capture
• Arrangement of logistical services for protocol-specific costs, including subcontracts and supplies
• Single IRB (sIRB) and Data Safety Monitoring Board (DSMB) associated costs
• Travel: The costs of travel to the NIH HEAL Annual Investigators' Meeting and up to 2 (two) NIH HEAL KIDS Pain-sponsored meetings over the award period
• Supplies and small equipment (itemized and justified)
• Other costs (itemized and justified)
• PEDP implementation costs, applicants may include allowable costs associated with PEDP implementation (as outlined in the Grants Policy Statement section 7: https://grants.nih.gov/grants/policy/nihgps/html5/section_7/7.1_general.htm).

The protocol budgets will consist of specific protocol-related allowances, capitated per subject enrolled in the trial. Either the applicant Clinical Site or the DCC should be designated as responsible for issuing protocol fund payments to the clinical sites involved in the clinical trial.

The awarded Clinical Site's facilities and administrative (F&A) rates on the initial competitive award will not be increased in future years due to changes in their negotiated rate agreements.

Total funding for clinical sites in the multi-site clinical trial depends on the base award to the applicant clinical site and reimbursements for approved protocol-related expenses. The overall provision of funds for the clinical trial protocol team is subject to the availability of NIH funding.

PHS 398 Cover Page Supplement

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

PHS 398 Research Plan

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

Specific Aims: Briefly describe the objectives/goals of the proposed clinical trial, including relevant scientific hypotheses and a statement of how the overall Scientific Team will contribute to the successful conduct and completion of the clinical trial to potentially advance the field and improve care for pediatric patients with acute pain.

Research Strategy:

The Research Strategy must present an overview of the state of the science, current status and relevance of the trial, a detailed discussion of the specific protocol, and the approach to data collection. Provide a brief description of study research objectives. The research strategy and objectives must be in alignment with the APCT program research objectives and scope outlined in "Section I. Funding Opportunity Description: Research Objectives and Scope.".

The following criteria must be addressed:

Significance. The significance of the proposed clinical trial and importance of the question must be clearly stated.

It is particularly important to provide a discussion of the evidence supporting equipoise. The application should make clear the need for and timeliness of the study with emphasis on how the results will address an evidence gap and therefore advance science. Include a description of how results will impact health or clinical care. A discussion of the costs and benefits of the study should be included for evaluation of the trial's significance.

Innovation: Describe how the proposed clinical trial challenges and seeks to shift current research or clinical practice paradigms. Describe how the proposed clinical trial offers innovative research activities such as ways to communicate, resource, promote collaborations, and recruit and retain participants. Describe any innovations in conducting multi-site pediatric pain research.

Approach: The research approach section should include a description of the supporting data, strategy, methodology, analyses, risk and project management, and the experimental approach. Include plans to address any weaknesses in rigor as key support.

Clinical Trial Management: Describe a trial management plan that will provide sufficient detail to demonstrate the ability to achieve the goals of the clinical trial on-budget and in the allotted time that will lead to successful management and mitigation of risks. The risk and management strategy will ensure that the activities of the clinical trial are performed, and that the scientific study leadership identify barriers, make timely responses, and optimize the allocation of limited resources to meet pre-defined study objectives. This description should include:

• Description of the project management team and levels of effort.
• Description of how the clinical sites and the DCC project management teams will integrate with one another.
• A risk assessment and management plan that addresses contingencies in the event that there is inadequate progress toward achieving the core milestones. The plan should identify a range of contingencies that could threaten study progress or feasibility and propose solutions using study resources.
• Key methodology and standard operating procedures governing resource management, study deployment, operations/execution, and study closure.
• How the clinical trial, in collaboration with the proposed DCC, will resolve fiscal and logistical issues in a timely manner, including plans to proactively evaluate and prioritize study risks, and issue corrective responses.

  Coordination of HEAL KIDS Program :

  The various clinical trials proposed under the U01 mechanism will have the Resource and Data Center (U24) as the centralized home for coordinating data related activities across the HEAL kids Pain research program. The RDC will be primarily responsible for coordinating and/or facilitating scientific workgroups, convening subject matter expert panels and providing general infrastructure to facilitate scientific collaboration between all HEAL KIDS Pain program awardees. In order to do this, the RDC will be responsible for the establishment and management of an Executive Committee of all participating clinical trial and DCC PDs/PIs to facilitate communication and decision-making for the HEAL KIDS Pain program. It is also anticipated that the RDC will support programs to encourage continued scientific discussion to address the current needs/gaps in pediatric pain research. Anticipate at least (one) 1 facilitated meeting of all interested parties in the first year of award, in addition to one (1) other smaller NIH requested meetings per year as needed, and at least quarterly executive meetings.

  Supporting Data: Describe the formative clinical studies (including any pilot studies) that are the basis for the proposed clinical trial. Include other research as appropriate to demonstrate that the approach chosen is justified. If the clinical trial is Phase III, include relevant data used to determine that the proposed trial includes adequate numbers of subgroups of participants to allow for separate and adequately powered analyses. Conceptualization and planning must have progressed to a stage sufficient to allow for an overall assessment of the likelihood of the success of the trial.

  Experimental Approach: Include critical attributes of conducting the clinical trial that are not already submitted as part of the PHS Human Subjects and Clinical Trials Information Form, including but not limited to, the following experimental approach items:

  • A detailed description and rationale for the research hypothesis(es)
  • The rationale for the specific design chosen
  • Evidence supporting that: 1) equipoise exists between the arms of the trial and 2) the intervention(s) or control arm(s) tested are not known to be inferior to the range of practice (or usual care) at the sites, in their community, and described in relevant standards of care
  • A detailed rationale explaining why the proposed study population is the most appropriate group to answer the research question(s)
  • Justification for all assessments including clinical, laboratory, physiological, behavioral, patient-centered, or other outcomes addressing the primary and secondary research question
  • A description of the use of patient reported outcomes as well as non-traditional data collection approaches (e.g., telephone, mobile devices, or web-based systems)
  • A description of the laboratory evaluations (as appropriate) and plans to implement and monitor Good Clinical Practices (GCP), Good Laboratory Practices (GLP) and Good Manufacturing Practices (GMP), as appropriate should be provided
  • A discussion of major challenges in implementing the study and how they will be addressed
  • A discussion of event rates and contingency plans if the effect size or event rate is underestimated

  Core Milestones

  Propose and justify milestones that will be subject to peer-review. A milestone is defined as a scheduled event in the project timeline that signifies the completion of a major project stage or activity. Milestones must be specific, relevant, measurable, results-focused, and time-bound, and should address timing of overall recruitment/enrollment and retention goals. The milestones must address accrual goals, and any other identified requirements for completion of the approved research supporting unambiguous study continuation decision each year.

  Core milestones of particular interest include, but are not limited to:

  • Complete finalized protocol and informed consent documents
  • DSMB review and approval of final protocol, template consent(s) and/or assent(s), and data and safety monitoring plan
  • IRB approval of final protocol and consent and/or assent
  • Enrollment of the first participant
  • 25% of sites activated
  • Enrollment of 25%, 50%, 75% and 100% of the projected recruitment for all study participants
  • Study closure and completion plans
  • Collection of data related to primary and secondary endpoints and database lock
  • Submission of primary manuscript to peer-reviewed scientific journal(s), dissemination of results, and data sharing

  Applicants should provide evidence of prior collaboration, available scientific expertise within the collaborating sites, evidence of follow-up capabilities (as evidenced by a commitment to following children for up to two years after discharge/completion of intervention), available additional clinical capabilities (e.g., research pharmacists, qualified nursing staff, imaging capabilities, laboratory facilities, etc.), and any additional special or unique strengths of the team that may be relevant to the clinical trial (Do not duplicate information included in Facilities and Other Resources).

  Applicants from institutions that have a Clinical and Translational Science Award (CTSA) or other funded pediatric research centers must describe the type and amount of support available from those resources for conducting the clinical trial at the clinical sites.

  Letters of Support: Include Letters of Support directly relevant to the proposed clinical trial. In addition, departmental and institutional commitments to participate in the proposed HEAL KIDS Pain clinical trial must be clearly documented with letters of support with appropriate individuals from the applicant institution and participating subcontracted clinical sites. Evidence of past support can also be cited. Letters of support from appropriate leaders of institutional component services necessary for successful completion of the clinical trial must be included in the application.

  Applicants from institutions that have a CTSA funded by NIH should plan to access a National Center for Advancing Translational Sciences' Trial Innovation Network (TIN) (https://trialinnovationnetwork.org), or other funded pediatric research centers as resources for conducting the proposed research and provide a letter of agreement that identifies the level and type of support from the CTSA program director, NCATS TIN director, or PD/PI of the pediatric resource center.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide.

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

All applicants planning research (funded or conducted in whole or in part by NIH) that results in the generation of scientific data are required to comply with the instructions for the Data Management and Sharing Plan. All applications, regardless of the amount of direct costs requested for any one year, must address a Data Management and Sharing Plan.

The HEAL Initiative has additional requirements that must be addressed in the Data management and Sharing plan. All HEAL-generated data must be shared through the HEAL Initiative Data Ecosystem following HEAL’s compliance guidance (https://heal.nih.gov/data/complying-heal-data-sharing-policy). Specifically, HEAL applicants must include:

• Plans to submit data and metadata (and code, if applicable) to a HEAL-Compliant data repository (https://www.healdatafair.org/resources/guidance/selection) and follow requirements of the selected repository
• Plans to register your study with the HEAL platform within one year of award (https://heal.github.io/platform-documentation/study-registration/)
• Plans to submit HEAL-defined study-level metadata within one year of award (https://github.com/HEAL/heal-metadata-schemas/blob/main/for-investigators-how-to/study-level-metadata-fields/study-metadata-schema-for-humans.pdf) and https://heal.github.io/platform-documentation/slmd_submission/).
• HEAL pain clinical studies must include plan to use HEAL core Common Data Elements (https://heal.nih.gov/data/common-data-elements). HEAL Initiative clinical studies that are using copyrighted questionaries are required to obtain licenses for use prior to initiating data collection. Licenses must be shared with the HEAL Clinical Data Elements (CDE) team and the program officer prior to use of copyrighted materials.
• 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 CDE Program (https://heal.nih.gov/data/common-data-elements) if applicable and relevant to their research.
• Studies using CDEs, regardless of whether they are part of the HEAL repository, will be required to report which questionnaires are being used.
• To the extent possible, HEAL awardees are expected to integrate broad data sharing consent language into their informed consent forms.

HEAL has developed additional details and resources to fulfill these requirement (https://www.healdatafair.org/resources/road-map).

Appendix: Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

• No publications or other material, with the exception of blank questionnaires or blank surveys, may be included in the Appendix.

PHS Human Subjects and Clinical Trials Information

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 SF424 (R&R) 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 SF424 (R&R) Application Guide must be followed.

The finalized protocol will require approval by the NICHD or participating IC or Center Program Official.

Section 2 - Study Population Characteristics

• 2.7 Study Timeline

The clinical trial is a 5-year effort. The study timeline should list milestones that indicate progress at critical junctures of the clinical trial. The timeline and milestones should be sufficiently objective to evaluate what will be achieved during the course of the project. Prior to award, NIH staff will negotiate with the PD(s)/PI(s) a final series of concrete milestones and associated dates for their achievement. In the event of lower than expected enrollment or poor retention of patients, the Data and Safety Monitoring Board will make recommendations to the PD(s)/PI(s) and/or NIH to increase enrollment or terminate the study. NIH Program Staff must approve these plans prior to implementation.

Section 3 - Protection and Monitoring Plans

• 3.3. Data and Safety Monitoring Plan (DSMP)

Describe the process that will be utilized to identify unanticipated problems and describe procedures for intervention discontinuation and stopping guidelines.

Each proposed clinical trial program/awardee is expected to develop, implement, and maintain an overall Data and Safety Monitoring Plan (DSMP), that includes support for a Data and Safety Monitoring Board (DSMB) as per NIH guidelines for clinical trials. The DSMP is for tracking and reporting all Serious Adverse Events (SAEs) and Adverse Events (AEs).

• The DSMP will be developed and distributed to participating clinical sites and include at least the following:
  1. SAE reporting forms, SOPs for processing AE data, and other appropriate instructions or manuals.
  2. The forms shall be developed in coordination with the site investigators, and after approval from Data and Safety Monitoring Board (DSMB). These documents shall conform to NIH guidelines.
• Each respective Data Coordinating Center that is associated with the clinical trial program will establish a system for identifying and receiving reports of unexpected AE and unexpected SAE and related safety information and prepare draft safety reports as deemed necessary for submission to site investigators, applicable Institutional Review Boards (IRBs), and the DSMB following the established federal regulations and guidelines.
• Each respective DCC shall maintain all necessary documentation of the activities, actions, deliberations, and recommendations of the DSMB.
• The DSMBs are expected to meet at least annually to review protocols, consent forms, interim safety data, efficacy data, and clinical trial progress such as the recruitment rate. A summary of all DSMB activities should be included in each of the DCC reports submitted to the NICHD.
• If approved by the Program Official, the grant shall provide support for the administrative needs of the DSMB, for example, scheduling meetings, teleconferences, and providing honoraria based on current Federal reimbursement rates.

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 SF424 (R&R) Application Guide must be followed.

PHS Assignment Request Form

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

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

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

4. Submission Dates and Times

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

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH 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 SF424 (R&R) Application Guide.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

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

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

7. Other Submission Requirements and Information

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

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

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

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile 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 SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

Applications must include annual milestones. Applications that fail to include annual milestones will be considered incomplete and will be withdrawn. Applications must include a PEDP submitted as Other Project Information as an attachment. Applications that fail to include a PEDP will be considered incomplete and will be withdrawn before review.

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.

Post Submission Materials

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

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:

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.

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).

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.

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.

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.

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by the Center for Scientific Review (CSR), 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.

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 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 appropriate national Advisory Council or Board. 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.
• Compliance with data management and sharing policies.

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.

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.

Report and ensure immediate public access to HEAL-funded publications

Publications resulting from NIH HEAL Initiative funded studies must be immediately publicly available upon publication. ?

• For manuscripts published in journals that are not immediately open access,?authors should arrange with journals in advance to pay for immediate open access. ?
• Costs to ensure manuscripts are immediately publicly available upon publication should be included in budget requests.??

Prior to publication, HEAL expects investigators to alert their program officers of upcoming manuscripts to ensure coordination of communication and outreach efforts.

Award recipients and their collaborators are required to acknowledge HEAL Initiative support by referencing in the acknowledgement sections of any relevant publication:

This research was supported by the National Institutes of Health through the NIH HEAL Initiative (https://heal.nih.gov/) under award number [include specific grant/contract/award number; with NIH grant number(s) in this format: R01GM987654].

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.

Should the applicant organization successfully compete for an award, recipients of federal financial assistance (FFA) from HHS will be required to complete an HHS Assurance of Compliance form (HHS 690) in which the recipient agrees, as a term and condition of receiving the grant, to administer their programs in compliance with federal civil rights laws that prohibit discrimination on the basis of race, color, national origin, age, sex and disability, and agreeing to comply with federal conscience laws, where applicable. This includes ensuring that entities take meaningful steps to provide meaningful access to persons with limited English proficiency; and ensuring effective communication with persons with disabilities. Where applicable, Title XI and Section 1557 prohibit discrimination on the basis of sexual orientation, and gender identity. The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-providers/provider-obligations/index.html and https://www.hhs.gov/civil-rights/for-individuals/nondiscrimination/index.html.

HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research. 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.

• For guidance on meeting the legal obligation to take reasonable steps to ensure meaningful access to programs or activities by limited English proficient individuals see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/fact-sheet-guidance/index.html and https://www.lep.gov.

• For information on an institution’s specific legal obligations for serving qualified individuals with disabilities, including providing program access, reasonable modifications, and to provide effective communication, see https://www.hhs.gov/civil-rights/for-individuals/disability/index.html.

• HHS funded health and education programs must be administered in an environment free of sexual harassment, see https://www.hhs.gov/civil-rights/for-individuals/sex-discrimination/index.html. For information about NIH's commitment to supporting a safe and respectful work environment, who to contact with questions or concerns, and what NIH's expectations are for institutions and the individuals supported on NIH-funded awards, please see https://grants.nih.gov/grants/policy/harassment.htm.

• For guidance on administering programs in compliance with applicable federal religious nondiscrimination laws and applicable federal conscience protection and associated anti-discrimination laws see https://www.hhs.gov/conscience/conscience-protections/index.html and https://www.hhs.gov/conscience/religious-freedom/index.html.

Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 and 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 45 CFR Part 75 and 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.

Recipients of this initiative will be expected to interact with recipients of the HEAL KIDS Pain initiatives within HEAL via NIH-sponsored workshops and meetings.

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

• Design and execution of the clinical trial protocol, supervision of personnel, interaction with the Institutional Review Boards, interaction with subcontracted clinical site PIs, grants management officials, DSMB, DCC, RDC, and the NIH
• Defining the objectives and approaches, planning, conduct, analysis, and publication of results, interpretations, and conclusions of studies conducted under the terms and conditions of the cooperative agreement award.
• Assuming responsibility and accountability to the applicant organization officials and to the NIH for the performance and proper conduct of the research supported under this NOFO in accordance with the terms and conditions of award, as well as all pertinent laws, regulations, and policies.
• Assuring their staff will maintain confidentiality of the information as developed by the clinical trials project team, including, but not limited to, study protocols, data analysis, conclusions, etc.
• Analyzing, publishing, and/or publicly releasing and disseminating results, data and other products of the study in a timely manner, concordant with the approved plan for making quality-assured data and materials available to the scientific community and the NIH, consistent with NIH policies and achieving the goals of the NOFO.
• Collection and transmission of data to the DCC, and ensuring required data is submitted to the HEAL KIDS Pain RDC
• Projecting research participant enrollment for the protocol during a specified time frame (continuation and level of funding will be based on actual enrollment)
• Participating in a cooperative and interactive manner with members of the clinical trial project team, the HEAL KIDS Pain program team, the NIH HEAL Initiative, and the designated NIH staff (e.g., Program Officer(s) and Project Scientist(s))
• Sharing data, materials, models, methods, information, and unique research resources that are generated by the project in concordance with NIH HEAL policies in order to facilitate progress.
• Complying with the processes and goals as delineated with the NOFO.
• Upon completion or termination of the research project, the recipients are expected to make all study materials and procedures broadly available (e.g., in the public domain) or making them accessible to the research community according to the NIH-approved plan submitted for each project, for making data and materials available to the scientific community and the NIH for the conduct of research. The Data Management and Sharing Plan should include a plan to accomplish this at the end of the study.
• 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 DHHS, PHS, and NIH policies.

A Clinical Trial Protocol Steering Committee (SC) may be formed (in consultation with the NIH Program Officer (PO), depending on the number of clinical sites involved). The purpose of the SC will be to achieve the goals of the team, to establish publication and dispute resolution policies, and common protocols.

The SC composition will be created in consultation with the NIH PO depending on the size and needs of the protocol team, but generally will be composed of the PD(s)/PI(s) of the awarded application, a core of clinical site PIs, the DCC Project Manager or PI, as well as designated NIH staff. It is expected that most decisions on the activities of the protocol team will be reached by consensus, however, if a vote is required, the voting procedures will be outlined in consultation with the NIH PO.

• The PD/PI or contact PD/PI in the case of multi-PD/PI awards, will serve as a voting member of the SC and will attend all meetings of the SC
• The recipient will be responsible for accepting and implementing the goals, priorities, procedures, protocols, and policies agreed upon by the SC and any related subcommittees.

Similarly, a HEAL KIDS Pain Executive Committee (EC) may be formed by the RDC (in consultation with the NIH Program Officer). The purpose of the EC will be to achieve the goals of the data harmonization, to establish SOPs for decision making and communication amongst the U01 recipients and the RDC.

• The EC composition will be created in consultation with the NIH PO but generally will be composed of the PD(s)/PI(s) of the U01 and U24 awarded applications, a core of clinical site study coordinators, the RDC Project Manager or PI, as well as designated NIH staff. It is expected that most decisions on the activities of the EC will be reached by consensus, however, if a vote is required, the voting procedures will be outlined in consultation with the NIH PO.
• The U01 recipient will be responsible for accepting and implementing the goals, priorities, procedures, protocols, and policies agreed upon by the EC and any related subcommittees.

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

The NIH Project Scientist(s) will provide technical assistance to the clinical trial protocol team. Specifically, the NIH Project Scientist will:

• Assist in the development of study protocols
• Assist in the development and review of capitation-based budgets, including the identification of study costs and special institutional needs
• Assist in the review and evaluation of each stage of the program before subsequent stages are started, in conjunction with the clinical trial project team, and NIH Program Official (see below) and make recommendations to enhance the scientific quality of the work.
• Assist in the reporting of results to the community of investigators and health care recipients
• Assist in the conduct of the trials and studies, including ongoing review of progress, possible redirection of activities to improve performance and cooperation, and frequent communication with other members of the protocol team
• Liaison with the NIH Project Officer and communication of progress and difficulties
• The NIH will name additional scientific consultants as necessary from within the NIH whose function will be to assist the Project Scientist(s) and protocol team in carrying out the goals and aims of the approved study. The NIH will have one vote (if voting body) regardless of the number of NIH personnel involved
• Have substantial scientific programmatic involvement in quality control, preparation of publications, research coordination and performance monitoring. The Project Scientist(s) will have the same access and privileges to any data generated by the grantee. The dominant role and primary responsibility for these activities resides with the recipients for the project as a whole, although specific tasks and activities in carrying out the studies will be shared among the recipients and the Project Scientist(s).
• Serve as a resource with respect to other ongoing NIH activities that may be relevant to the protocol to facilitate compatibility and avoid unnecessary duplication of effort.
• Serve as a non-voting member of the HEAL KIDS PAIN Executive Committee. The U24 Project Scientist will serve as the voting member of the committee, as only one NIH vote is allowed, regardless of the number of NIH personnel involved.
• Review procedures for assessing data quality and monitor study performance
• Serve as a co-author on study publications. In general, to warrant co-authorship, the NIH staff must have contributed to one or more of the following areas: (a) design of the interventions being tested; (b) performance of significant portions of the activity; (c) participation in analysis and interpretation of study results; and (d) preparation and authorship of pertinent manuscripts.
• 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:

• All parties will agree to work collaboratively in all activities of the HEAL KIDS Pain program, throughout the course of the award period.
• Participating in protocol-related meetings, and all HEAL KIDS Pain program, and NIH HEAL Initiative investigator meetings and other required meetings.
• The Steering Committee, if required, will be the governing body of the study. The Steering Committee chair will be select by the steering committed via vote.
• The NIH Project Scientist will be a voting member of the Steering Committee. The Program Officer(s) and other members of the project team will be non-voting participants.
• The NIH Project Scientist may serve on the Executive Committee, as will the Project Scientist for the U24; however, only one NIH voting member on the Executive Committee.
• The SC may, as it deems necessary, invite additional, non-voting scientific consultants to meetings at which research priorities and opportunities are discussed. The NIH reserves the right to augment the expertise of the SC when necessary.
• All responsibilities are divided between recipients and NIH staff as described above.

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

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.

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

• 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 is complete.
• The NIH HEAL Initiative expects data used in publications to be submitted to repositories at the time of or prior to publication, and no later than the end of the project period.

5. 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, HEALrecipients 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/.

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.

• Recipients will provide updates at least annually on implementation of the PEDP.

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 45 CFR Part 75.301 and 2 CFR Part 200.301.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), 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 the threshold. See the NIH Grants Policy Statement for additional information on this reporting requirement.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and 2 CFR Part 200.113 and Appendix XII to 45 CFR Part 75 and 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 (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 and 2 CFR Part 200 Award Term and Condition 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: [email protected] (preferred method of contact)
Telephone: 301-480-7075

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: [email protected]

Tammara Jenkins, MSN, RN, PCNS-BC
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 240-461-7952
Email: [email protected]

Perdita Taylor-Zapata, MD
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-496-9584
Email: [email protected]

Beda Jean-Francois, Ph.D.
National Center for Complementary & Integrative Health (NCCIH)
Phone: 202-313-2144
Email: [email protected]

Devon Oskvig, Ph.D.
National Institute on Aging (NIA)
Phone: (301) 496-9350
E-mail: [email protected]

Karen A. Kehl, PhD, RN
National Institute of Nursing Research
Telephone: 301-594-8010
Email: [email protected]

William P Tonkins, Dr. PH, J.D.
NHLBI - NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
Phone: 301-594-4979
E-mail: [email protected]

Rebecca Hommer, MD
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-827-2257
Email: [email protected]

Brennan Parmelee Streck, PhD, RN, MPH
National Cancer Institute (NCI)
Phone: 301-357-0516
Email: [email protected]

Dana K Andersen, MD
NIDDK - NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
Phone: 410-868-0638
E-mail: [email protected]

Dena Fischer, DDS, MSD, MS
NIDCR - NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH
Phone: (301) 594-4876
E-mail: [email protected]

Rebecca Lenzi, PhD
NIAMS - NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
Phone: (301) 402-2446
E-mail: [email protected]

Examine your eRA Commons account for review assignment and contact information (information appears two weeks after the submission due date).

Barbara Hodgkins
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-827-5306
Email: [email protected]

Debbie Chen
National Center for Complementary and Integrative Health (NCCIH)
Phone: 301-594-3788
Email: [email protected]

Kathleen Moy
National Institute on Aging (NIA)
Phone: 301.827.2856
E-mail: [email protected]

Kelli Oster
National Institute of Nursing Research (NINR)
Telephone: 301-594-2177
Email: [email protected]

Nina Hall
NHLBI - NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
Phone: 301-435-0710
E-mail: [email protected]

Chief Grants Management Officer
National Institute of Neurological Disorders and Stroke (NINDS)
Email: [email protected]

Sean Hine
National Cancer Institute (NCI)
Phone: 240-276-6291
Email: [email protected]

Elizabeth Gutierrez
NIDDK - NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
Phone: 301-594-8844
E-mail: [email protected]

Diana Rutberg, MBA
NIDCR - NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH
Phone: (301) 594-4798
E-mail: [email protected]

Sarisa Kowl
NIAMS - NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
Phone: 301-594-1921
E-mail: [email protected]

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 45 CFR Part 75 and 2 CFR Part 200.