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

This notice of funding opportunity (NOFO) from the NIH’s Helping to End Addiction Long-term (HEAL) Initiative aims to support research aimed at holistic understanding of inter-individual or between-person differences in human pain conditions, focusing  on ‘Whole Person Health’ and enhancing pain treatment and management strategies . The goal of this NOFO is to support studies that focus on the collection of clinical and/or preclinical data to enable evidence-based modeling and understanding of inter-individual differences and/or heterogeneity of pain occurring with use of pain therapy/management, or with conditions such as a second pain condition, a comorbid health condition, a comorbid mental health condition, or conditions of use / misuse of opioids, alcohol or other substances. Development and implementation of novel, multidisciplinary research approaches, inclusion of different study populations, and inclusion of investigators with complementary expertise are highly encouraged to fulfill the project and program goals. 

Rigorous data-driven and evidence-based research approaches supported under this NOFO are expected to provide better understanding of biological underpinnings of inter-individual differences, heterogeneity, and stratification of persons with lived pain experience. Research accomplishments in this area will also strengthen cross-cutting research and an improved understanding of the impact of pain on substance use / misuse or mental health and vice versa, and the data & models generated can be utilized to back-translate to preclinical models or ex vivo studies. Furthermore, accomplishments from these research programs will generate significant scientific knowledge that will critically contribute to an array of scientific discovery and pain therapeutics development programs in the NIH HEAL Initiative. In the long-term, these accomplishments will accelerate evidence-based solutions for the development of effective individualized pain therapeutics & management strategies, and move us closer to precision pain medicine.   

Background

More than 25 million Americans suffer from daily chronic pain, a highly debilitating medical condition that is complex and difficult to manage. In recent decades, there has been an over-reliance on the prescription of opioids for chronic pain despite their poor ability to improve function and high addiction liability. This contributed to a significant and alarming epidemic of opioid addiction and overdose deaths. Inter-individual differences in pain sensitivity and analgesic responses to opioids and other therapeutics contribute to these complex problems. Innovative scientific solutions to develop alternative pain treatment options are critically needed, including studies encompassing molecular, genetic, environmental and psychosocial factors that contribute to mechanisms underlying inter-individual differences in pain sensitivity and analgesic responses.

The NIH HEAL Initiative:

This NOFO is part of the NIH HEAL Initiative ’s goal 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 and periodic updates about the NIH HEAL Initiative is available at: https://heal.nih.gov/.

The NIH HEAL Initiative aims to identify new, safer treatment options for pain management to improve quality of life and reduce the number of people exposed to the risks of opioids. Providing effective pain treatment and management remains a critical challenge in addressing the ongoing opioid epidemic. Contributing to this challenge, pain is a subjective and a highly personal experience. A multitude of factors, including, but not limited to, psychosocial, demographic, genetic, and environmental factors, as well as an interplay between two or more of these factors, results in pain experiences that are highly individualized. There is a lack of comprehensive understanding on inter-individual differences in pain experiences and severity, both in terms of understandings at clinical feature/phenotypic level and the underlying preclinical/mechanistic bases. Preclinical models have enhanced the understanding of pathophysiological mechanisms associated with pain, yet treatment strategies remain inadequate, and most existing preclinical models have lacked or largely failed to address inter-individual differences in pain sensitivity and treatment responses, including environmental, molecular, genetic and psychosocial factors contributing to those. Individuals frequently present with two or more pain conditions along with additional comorbidities (i.e., health or mental health conditions, opioid use or misuse, alcohol use or misuse, or substance use or misuse) which might be a risk factor for pain or could influence treatment outcomes. The Federal Pain Research Strategy report identified the need to understand the biological underpinnings of inter-individual differences as a critical gap that needs to be addressed to deliver evidence-based solutions toward precision pain medicine (https://www.iprcc.nih.gov/node/8/federal-research-pain-strategy). This NOFO, as part of a suite of NIH HEAL Initiative programs and funding opportunities, aims at enhancing pain management through supporting research on understanding inter-individual differences in human pain and comorbidities by encouraging collaborative investigations involving investigators with complementary expertise.

Research Objectives

This NOFO encourages investigators to pursue challenging research addressing inter-individual or between-person differences observed in pain perception, pain severity, NIH HEAL core pain domains, treatment effectiveness/responsiveness, and/or the impact of comorbidities, including a biopsychosocial context to conceptualize and study inter-individual differences in responses to pain and its treatment, focusing on ‘whole person health’. The core pain domains include: pain intensity, pain interference, physical functioning/quality of life, sleep, pain catastrophizing, depression, anxiety, global satisfaction with treatment and substance use screener. Details of these core pain domains and NIH HEAL pain core common data elements (CDE) can be found at https://heal.nih.gov/data/common-data-elements. Whole Person Health refers to looking at the whole person, not just separate organs or body systems, and considering multiple factors that promote either health or disease.   

To be considered responsive to this NOFO, applications should focus on the collection of clinical and/or preclinical data to enable evidence-based modeling and understanding the biological mechanisms and/or psychosocial aspects of pain occurring with:

1. Use of pain therapy/management, or
2. A second pain condition, or
3. A comorbid health condition, or
4. A comorbid mental health condition, or
5. Opioid use / misuse, or
6. Alcohol use / misuse, or
7. Substance use / misuse.

Proposed research studies should develop strategies, taking into consideration plans to:

1. Generate data to stratify individuals with lived pain experience, based on pain conditions along with use of pain therapy/management and/or comorbidity (i.e., health or mental health condition, opioid use or misuse, alcohol use or misuse, or substance use or misuse).
2. Utilize rigorously-collected clinical and/or preclinical data to create novel mathematical/statistical and/or computational models to identify and characterize inter-individual differences in people with lived pain experience.
3. Utilize clinical and/or preclinical data and the generated/developed models to provide a better understanding of the biological underpinnings and mechanisms underlying inter-individual differences towards patient stratification.
4. Create a plan to disseminate information on data and models, compliant with the HEAL Initiative Public Access and Data Sharing Policy, and consistent with the NIH Data Management and Sharing Policy”.

Applicants are encouraged to develop and implement a rigorous, multidisciplinary, data-driven, and evidence-based research approach, alongside inclusion of investigators with complementary expertise that will result in the development of mathematical/statistical/computational models, as well as better understanding of the biological and psychosocial underpinnings of inter-individual differences and stratification of persons with lived pain experience, which would lead to enhanced and individualized pain management. Projects that seek to study inter-individual differences in pain in specific populations such as women, children, older adults, and other populations that are underserved or populations with health disparity will also be responsive to this. Input from patients and caregivers on the goals of the project is highly encouraged. 

Applications Not Responsive to this NOFO

The following application types will be considered non-responsive to this NOFO and withdrawn from consideration without review:

• Applications with a focus on conducting pain and/or disease biomarker and/or psychosocial biomarker studies.
• Applications on conducting and collecting longitudinal clinical data on biosignatures and/or associated biopsychosocial factors, without a major focus & detailed plans on the generation/development of novel mathematical/statistical and/or computational models to identify and characterize inter-individual differences in people with lived pain experience.
• Applications with a focus on development of in vitro and/or ex vivo biological model systems to study inter-individual differences in pain.
• Applications consisting of studies that involve discovery, development and optimization of therapeutics, including therapeutics aimed at addressing inter-individual differences in pain and comorbidities. For applications proposing translational projects, applicants are encouraged to consider several programs and   NOFOs listed on the NIH HEAL website at https://heal.nih.gov/funding/open.
• Applications consisting of studies that are aimed at evaluating potential therapeutic agent(s) or device for efficacy or safety studies.
• Applications consisting of studies that are aimed at developing new clinical pain management strategy and/or conducting clinical trial with modifications to currently approved clinical pain management strategies, utilizing already available data or data collected from proposed studies.
• Applications consisting of clinical trials designed primarily to determine the safety, tolerability, and/or clinical efficacy/effectiveness of an intervention.
• Applications focused primarily on technology development towards collection and modeling of data.
• Clinical trials that seek to answer specific questions about safety, tolerability, clinical efficacy, effectiveness, clinical management, and/or implementation of pharmacologic, behavioral, biologic, surgical, or device (invasive or non-invasive) interventions, preventive, therapeutic, and services interventions.

For applications proposing a clinical trial, note the following definitions and restrictions for this funding announcement:

• Clinical trials are research studies in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes. For this funding announcement, only the following types of clinical trials will be accepted:
  • Mechanistic trials, defined as studies designed to understand inter-individual differences in biological or behavioral process(s), the pathophysiology of pain and co-morbid condition to be studies, or the mechanism of action of an intervention (i.e., how an intervention works, but not if it works or is safe).
  • Basic Experimental Studies with Humans (BESH), defined as basic research studies involving humans that seek to understand the fundamental aspects of inter-individual differences in pain and co-morbid conditions.
• For further clarification on how NIH defines the different types of clinical trials, please refer to the following resources:
  • NOT-OD-15-015: Notice of Revised NIH Definition of “Clinical Trial”
  • NIH's Definition of a Clinical Trial
  • Decision Tree for NIH Clinical Trial Definition
  • Guidance for Basic Experimental Studies with Humans (BESH) Funding Opportunities
  • NIH Definition of Clinical Trial Case Studies

For applications proposing translational projects, applicants are encouraged to consider several programs and NOFOs listed on the NIH HEAL website at https://heal.nih.gov/funding/open.

Some important points to consider before applying:

Rigor and Transparency

NIH strives for rigor and transparency in all research it funds. For this reason, the NIH HEAL Initiative explicitly emphasizes the NIH application instructions related to rigor and transparency (https://grants.nih.gov/policy/reproducibility/guidance.htm) and provides additional guidance from individual NIH ICs to the scientific community. For example, the biological and clinical rationale for the proposed experiments and/or data collection and data modeling goals must be based on rigorous and robust supporting data, which means that data should be collected via methods that minimize the risk of bias and be reported in a transparent manner. If previously published or preliminary studies do not meet these standards, applicants should address how the current study design addresses the deficiencies in rigor and transparency. Proposed experiments and/or data collection and data modeling approaches should likewise be designed in a manner that minimizes the risk of bias and ensures validity of experimental results.

Clinical Trial Accrual Policy

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.

HEAL Core Common Data Elements (CDE)

The NIH HEAL Initiative research portfolio spans a broad array of data types that are a rich resource for future studies. Maximizing the value of data collected through the initiative is part of the initiative’s collective responsibility, given the magnitude of the opioid crisis and needs of individuals experiencing pain and addiction. To facilitate cross-study comparisons and improve the interpretability of findings, clinical pain research recipients  collaborate and agree to use common data elements for patient-reported outcomes (PROs). All HEAL studies collecting human subjects data and planning to use CDEs (even studies outside the clinical pain research portfolio) are strongly encouraged to search for applicable CDEs within the HEAL database, and use questionnaires from this database if possible. Studies using CDEs, regardless of whether they are part of the HEAL repository, will be required to report which questionnaires are being used. Details of HEAL CDEs can be found at https://heal.nih.gov/data/common-data-elements. 

HEAL pain clinical studies must include plan to use HEAL core Common Data Elements (CDE) (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 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 subjects are expected to use questionnaires by the HEAL CDE program, if applicable and relevant to their research.

Plan for Enhancing Diverse Perspectives 

The NIH recognizes that diverse teams working together and capitalizing on innovative ideas and distinct perspectives outperform homogenous teams.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. To support the best science, the NIH HEAL Initiative encourages inclusivity in research. Examples of structures that promote diverse perspectives include but are not limited to:

• Transdisciplinary research projects and collaborations
• Engagement from different types of institutions and organizations (e.g., research-intensive, undergraduate-focused, minority-serving, community-based)
• Individual applications and partnerships that enhance geographic and regional heterogeneity
• Investigators and teams composed of researchers at different career stages
• Participation of individuals in research study and/or investigating team, from diverse backgrounds, including groups historically underrepresented in the biomedical, behavioral, and clinical research workforce (see NOT-OD-20-031), such as underrepresented racial and ethnic groups, those with disabilities, those from disadvantaged backgrounds, and women
• Project-based opportunities to enhance the research environment to benefit early- and mid-career investigators

This NOFO requires a Plan for Enhancing Diverse Perspectives (PEDP) as part of the application (see further below). Applicants are strongly encouraged to read the NOFO instructions carefully and view the available PEDP guidance material.

Applications must include a Plan for Enhancing Diverse Perspectives (PEDP) submitted as Other Project Information as an attachment (see Section IV). The PEDP will be assessed as part of the scientific and technical peer review evaluation.

Engaging People with Lived Experience and other Collaborators

People with lived experience (e.g., patients, patient advocates, caregivers, families, community leaders) have important insights that can improve meaningful outcomes, uptake of research findings, and health equity across the continuum of research from basic through implementation studies. The perspectives of other relevant collaborators (e.g., health service providers, payors, public health agencies, community-based organizations, biotech, pharma) can further improve research impact. The NIH HEAL initiative strongly encourages applicants to specify their plan for meaningful engagement of people with lived experience and other collaborators in the research process. Meaningful engagement will vary with the focus of the research but should at minimum ensure that researchers are connecting with relevant collaborators and incorporating their perspectives throughout the conception, implementation, and dissemination of the research. Meaningful engagement should address what the researchers will learn and how the people with lived experience and/or collaborators will benefit from the partnership. In addition, NIH encourages outreach to people with lived experience from populations who experience health disparities. See this resource for more information in engaging people with lived experience: https://aspe.hhs.gov/lived-experience).

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 recipients will cooperate and coordinate their activities after awards are made by participating in Program Director/Principal Investigator (PD/PI) meetings, including an annual HEAL Investigators Meeting, as well as other activities. In addition, recipients are expected to participate in an annual meeting that brings together early-career pain researchers funded at NIH and their mentors. This meeting will be executed by the Coordinating Center for National Pain Scientists Career Development (CCNPS). The purpose of these meetings is to enhance mentorship and training, to collaborate with pain researchers across the continuum of pain research, and build relationships to enhance research and potentially collaborate with researchers outside of their institution. For more information on the CCNPS, please review RFA-NS-22-060.

Prior Consultation with NIH HEAL Initiative Program staff

The NIH HEAL Initiative intends to fund a limited number of applications for this NOFO. Therefore, consultation with relevant staff at least 6 weeks prior to the application due date is strongly encouraged. Once applicants have identified overall program objectives and PD/PI participants, HEAL Initiative staff may be able to advise applicants whether the proposed research goals and strategy meets the goals of the NIH HEAL Initiative and mission of the ICs, whether it addresses one or more high priority research areas, and whether it is appropriate for this NOFO. A proposed collaborative program that is closely related to the goal of a PD/PI's existing NIH-funded research might require that funding be relinquished to avoid overlap. HEAL Initiative staff will not evaluate the technical and scientific merit of the proposed program in advance; technical and scientific merit will be determined during peer review process using the review criteria indicated in this NOFO. 

NIH Institute and Center Interests and Guidance

National Institute of Neurological Disorders and Stroke (NINDS)
NINDS is interested in understanding inter-individual or between-person differences in pain conditions that are related to diseases and disorders of the nervous system within the mission of NINDS. These disorders include, but are not limited to headache, migraine, post-stroke pain, neuropathic pain, pain following traumatic brain injury, pain associated with spinal cord injury, pain associated with Alzheimer’s disease and other dementias, pain associated with Parkinson’s Disease and chronic overlapping pain conditions. NINDS, as part of NIH, strives for rigor and transparency in all research it funds. For this reason, NINDS explicitly emphasizes and provides supplemental guidance to NIH application instructions related to rigor and transparency (https://grants.nih.gov/policy/reproducibility/guidance.htm). For example, the biological rationale for the proposed experiments must be based on rigorous and robust supporting data, e.g., by minimizing the risk of bias and transparently reporting methods and results as described at https://www.ninds.nih.gov/Funding/grant_policy. As stated in the NIH application guidelines, if previously published or preliminary studies do not meet these rigor standards to an acceptable degree, applicants should address how the current study design addresses the deficiencies. Proposed experiments should likewise be designed in a manner that minimizes the risk of bias and ensures validity and transparency of experimental results.

National Cancer Institute (NCI)
NCI is interested in research projects aimed at understanding inter-individual or between-person differences in pain conditions related to cancer and cancer treatment. NCI is also interested in research projects looking at cancer as a comorbidity to treatment-related pain (for example, seeking to understand the impact of tumor type on peripheral neuropathy). Pain conditions of interest include, but are not limited to: bone cancer pain, oral cancer pain, metastasis-related pain, post-surgical pain, radiation pain, aromatase inhibitor-induced arthralgia, chemotherapy-induced peripheral neuropathy, and immunotherapy-related pain.

National Center for Complementary and Integrative Health (NCCIH)
NCCIH is interested in investigating inter-individual or between-person differences in response to complementary and integrative health approaches to treatment of pain conditions and/or their comorbidities and to promotion of well-being and whole person health. Complementary health approaches include a broad range of practices and interventions that are not typically part of conventional medical care. They can be classified by their primary therapeutic input, including nutritional (e.g., special diets, dietary supplements, herbs, probiotics, and microbial-based therapies), psychological (e.g., meditation, hypnosis, music-based interventions, relaxation therapies), physical (e.g., acupuncture, massage, chiropractic manipulation, other force-based manipulations, or devices related to these approaches), or a combination of psychological and physical (e.g., yoga, tai chi, dance therapies, some forms of art therapy such as music-based interventions). 

National Heart, Lung, and Blood Institute (NHLBI)
The NHLBI is interested in collaborative research that furthers our understanding of the biology of pain conditions within the mission of NHLBI.  Topics of special interest include, but are not limited to, pain associated with blood diseases such as sickle cell disease, hemophilia, deep venous thrombosis; pain associated with cardiovascular diseases such as peripheral artery disease and vasculitis; pain associated with the symptoms and treatment of lung disease such as severe cough, pleurisy, tube thoracostomy, and mechanical ventilation; and pain associated with heart, lung or bone marrow transplantation or gene and cell therapy procedures.

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 Government

• Eligible Agencies of the Federal Government, including NIH Intramural Programs
• 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)

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.

Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are 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 registration; all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov – Applicants must have an active SAM registration in order to complete the Grants.gov registration.

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

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

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with their organization to develop an application for support. Individuals from diverse backgrounds, including those from 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.

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.

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:

D.P. Mohapatra, Ph.D.
Telephone: 301-496-9964
Fax: 301-402-2060
Email: dp.mohapatra@nih.gov

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.

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

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

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

Facilities and Other Resources:

Institutional, and other resources that constitute the environment for this research program should be described. New cost-sharing commitments are not required. Some examples of institutional environment could include recruitment and salary support of new faculty or professional staff positions to support the resources, startup packages, space renovations for team investigators, new facilities, dedicated equipment for research and resource components, dedicated budget lines or facilities for a team consortium, dedicated use of commercial products and technologies, equipment and technology contributions from commercial collaborators, etc. Summarize how the facilities and resources are complimentary and critical to this application. 

• In addition to standard items, describe existing facilities and/or other resources (such as existing institutional shared resource cores) available to the proposed project.
• As applicable and pertinent to the proposed research, describe partnerships (e.g., with industrial entities) that will provide relevant capabilities. 

Other Attachments:

Plan for Enhancing Diverse Perspectives (1-page maximum):

All applicants must include a summary of strategies to advance the scientific and technical merit of the proposed project through expanded inclusivity. The plan for enhancing diverse perspectives (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 traditionally 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 questions(s).
• Publication plan that enumerates planned manuscripts and proposed lead authorship.
• Outreach and planned engagement activities to enhance recruitment of individuals from diverse backgrounds, including those from underrepresented groups in research.

IRB Communications (Optional–5 pages maximum):

This attachment should be entitled "IRB-Communications.pdf". Applicants should submit relevant approval letters and associated attachments. Applications that exceed this page limit will be withdrawn.

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

R&R 

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

Research Budget: To be successful, projects of this level of complexity are expected to require significant effort from all PDs/PIs and key personnel involved. Generally, the PD/PI must devote at least 2.4 person months (i.e., the equivalent of 20% effort on a full-year appointment, 26.7% on a 9-month appointment, or 40% on a 6-month appointment) or for MPIs a combined effort of 2.4 person months throughout the duration of the award. The total research effort should include their combined research effort at all institutions where the PD/PI holds an appointment, should be expressed in person-months, and should not include time expended towards teaching, administration not directly related to the PD's/PI's research, and/or clinical duties. Efforts cannot be reduced below this level during the entire project period.

Certain supporting functions such as equipment, animal research costs, and clinical research costs may be requested if well justified and unique to the institution(s) involved. Within the research budget, equipment, including data sharing and management systems, can be included if well justified. Equipment that duplicates existing institutional or regional shared facilities that are available to investigators must be identified and the proposed duplication should be well justified.  Applicants should consider the need to ramp-up projects of this complexity, and propose annual budgets accordingly. Do not request inflationary increases in the overall budget or any of the budget categories. Changes in budget should reflect changes in activities required by the science.

Data sharing costs:

• Applicants may include costs associated with preparing and submitting data to a data archive per NOT-OD-21-015.

R&R Subaward Budget

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

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

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

Specific Aims:

In the single Specific Aims attachment, briefly provide the context for the proposed set of studies, with an emphasis on understanding inter-individual differences observed in pain perception, pain severity, NIH HEAL core pain domains, treatment effectiveness/responsiveness, and/or the impact of comorbidities, including a biopsychosocial context to conceptualize and study inter-individual differences in responses to pain and its treatment. In addition, the major objectives of the proposed study must be stated, including the technical questions to be answered towards understanding and addressing inter-individual differences in pain conditions and co-morbidities, comprehensive data collection goals and mathematica/statistical/computational model development-validation strategies.

Research Strategy:

The Research Strategy must fully describe the biomedical problem being addressed, its significance within the relevant scientific field(s), and how successful accomplishment of the goals will provide substantial scientific advances in understanding inter-individual differences in human pain conditions and co-morbidities. The research strategy must thoroughly describe the specific human pain condition(s) and co-morbidities being studied, what is lacking in the biological and/or psychosocial understanding of those conditions, and what challenges exist in the clinical management of pain and co-morbidities in the context of inter-individual differences.

The Research Strategy must describe how the proposed project will enable the applicants to challenge existing paradigms, overcome long-standing roadblocks to progress, and/or develop new synergies between different scientific fields to understand the biological and/or psychosocial underpinnings of inter-individual differences in human pain conditions and co-morbidities. Applications must thoroughly describe the goals and significance of the proposed project within the relevant scientific field(s), the underlying premise and scientific foundation of the project, the rigor and status of prior research, current obstacles and challenges, experimental rationale, approaches, steps taken to assure scientific rigor, and how the proposed data collection and data modeling approach and outcomes will be transformative and/or enable major advances in understanding inter-individual differences in human pain conditions and co-morbidities. The research strategy must present how innovative combinations of scientific fields, research approaches, mathematical/statistical/computational technologies and/or intellectual viewpoints will enable the project's goals to be achieved. Innovative solutions by any means can be proposed.

Rigor and Transparency: The NIH HEAL Initiative urges investigators to follow the NIH guidance for rigor and transparency in grant applications (https://grants.nih.gov/policy/reproducibility/guidance.htm) and additionally recommends the research practices described by individual NIH ICs. This will ensure that robust experiments are designed, potential experimenter biases are minimized, results and analyses are transparently reported, and results are interpreted carefully. These recommended research practices include, where applicable, expressing clear rationale for the chosen model(s) and primary/secondary endpoint(s), describing tools and parameters clearly, blinding, randomizing, ensuring adequate sample size, pre-specifying inclusion/exclusion criteria, appropriately handling missing data and outliers, implementing appropriate controls, preplanning analyses, and using appropriate quantitative techniques. It is also strongly recommended to indicate clearly the exploratory vs. confirmatory components of the study, consider study limitations, and plan for transparent reporting of all methods, analyses, and results so that other investigators can evaluate the quality of the work and potentially perform replications.

Investigators must indicate whether data presented or cited in the application as key support for the proposed work were collected, analyzed, and reported in a rigorous and transparent manner as indicated above. A plan to address any ambiguity, weaknesses, or limitations in the prior research must be included in the application. Proposed experiments and data collection types must similarly adhere to these high standards of rigor and transparency.

If proposing a mechanistic trial: Applicants must describe the rigor, robustness, and transparency of supporting data that are being used to justify the proposed mechanistic trial and address any gaps identified. For all trials, the rationale for the trial design, population(s) and hypotheses being tested, and control groups must be described. Potential biases and/or challenges in the study design and protocol must be identified and addressed. For Basic Experimental Studies involving Humans (BESH), the application must describe and address how the expected effect size relates to biologically meaningful differences.

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.

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/. 

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.

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.
  • 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.
  • At the completion of the study and/or when prepared to make the final data deposits in the repositor(ies) of choice, ensure your study registration (https://heal.github.io/platform-documentation/study-registration/) is complete. 
  • 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.
• Plans to register your study with the HEAL platform within one year of award (https://heal.github.io/platform-documentation/study-registration/).
  • This process will connect the Platform to information about your study and data, including metadata, and identify the selected repository. HEAL requests initial submission within one year of award, with annual updates, and to be updated in accordance with any release of study data.
• 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/). 
  • Some of the required study-level metadata will be auto-populated as part of the registration process.
• 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 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.  
• To the extent possible, all other (non-pain) HEAL studies conducting clinical trials or research involving human subjects 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.  
• 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 requirements (https://www.healdatafair.org/resources/road-map). 

To maximize discoverability and value of HEAL datasets and studies, and facilitate data integration and collaboration, applications submitted in response to this NOFO are strongly encouraged to incorporate standards and resources where applicable:

• Applicants are encouraged to ensure that data collected by the study conform to Findable, Accessible, Interoperable, and Reusable (FAIR) principles.
• Applicants are specifically encouraged to incorporate into their planning, an alignment with the guidelines, principles and recommendations developed by the HEAL Data Ecosystem, including but not limited to preparing data to store in selected specified repositories, applying minimal metadata standards, use of core HEAL Clinical Data Elements (CDEs, https://heal.nih.gov/data/common-data-elements), and other necessary requirements to prepare data to connect to the HEAL Data Ecosystem.
• All new HEAL clinical pain studies are required to submit their case-report forms/questionnaires to the HEAL Clinical Data Elements (CDE) Program. The program will create the CDE files containing standardized variable names, responses, coding, and other information. The program will also format 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)), which “require[s] Federal agencies to make their electronic and information technology accessible to people with disabilities.” 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 CDE team and the program officer prior to use of copyrighted materials. For additional information, visit the HEAL CDE Program.
• To the extent possible, HEAL awardees are expected to integrate broad data sharing consent language into their informed consent forms and align study consent language with data access and re-use requirements as defined by repository HEAL investigators select to store their HEAL data long-term.

The NIH notices referenced below provide additional NIH guidance that should be considered in developing a strong data management and sharing plan. The list is instructive but not comprehensive.

• Elements of an NIH Data Management and Sharing Plan (NOT-OD-21-014)
• NIH has provided guidance around selecting a repository for data generated by NIH-supported research and has developed desirable characteristics for all data repositories (NOT-OD-21-016).
• NIH encourages the use of data standards including the PhenX Toolkit (www.phenxtoolkit.org) (for example, see NOT-DA-12-008, NOT-MH-15-009)
• Data should be organized according to a standard model that is widely accepted within the field. An example for the clinical research studies would be the OMOP Common Data Model, which has also been successfully adapted for use with observational (including survey) studies more generally. In addition, the HL7 FHIR (Fast Healthcare Interoperability Resources) standard (NOT-OD-19-122) may facilitate the flow of data with EHR-based datasets, tools, and applications.
• NIH encourages clinical research programs and researchers to adopt and use the standardized set of data classes, data elements, and associated vocabulary standards specified in the United States Core Data for Interoperability (USCDI) standards, as they are applicable (NOT-OD-20-146). Use of the USCDI can complement the FHIR standard and enable researchers to leverage structured EHR data for research and enable discovery. In addition to USCDI, OMOP, and FHIR standards for enhanced interoperability, investigators and data centers should align their data collection and management practices with recommended guidance emerging from the HEAL CDE and Data Ecosystem programs.

Awardees conducting research that includes collection of genomic data should incorporate requirements under the NIH Genomic Data Sharing Policy (NOT-OD-14-124, NOT-OD-15-086).

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

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, with the following modifications to designated sections below.

Section 3 - Protection and Monitoring Plans

3.3 Data and Safety Monitoring Plan (DSMP, for applications that include a mechanistic trial or BESH trial)

Attachment: DSMP: Applicants must submit a data safety and monitoring plan (DSMP) and should consider Guidelines and Policies for Monitoring Clinical Research in the formation of the plan as required by the appropriate IC. Applicants should:

• (In addition to the general guidelines at https://grants.nih.gov/grants/how-to-apply-application-guide/forms-h/research-forms-h.pdf) include an adequate description and justification of safety risks to participants that includes risks incurred during the trial. This description should incorporate how risks will be mitigated.
• Include adequate scientific justification for inclusion/exclusion criteria as defined in NOT-OD-18-014. 
• Describe plans to incorporate an independent committee to evaluate data safety and monitor patient safety, including what expertise will be included (https://www.ninds.nih.gov/Funding/Apply-Funding/Application-Support-Library/NINDS-Guidelines-Data-and-Safety-Monitoring).
• Describe any plan to address cybersecurity and confidentiality of participants’ personal data (if applicable).

Section 4 - Protocol Synopsis 

4.3 Statistical Design and Power

Attachment: Statistical Analysis Plan (SAP) for analyses specified in the study protocol: Applicants should provide a SAP for analyses specified in the study protocol. Include the rationale for how missing data will be handled; and futility; rationale for recalculation of the sample size midway through the trial (if applicable); and other measures to ensure rigor and transparency of the analysis. Sufficient details should be provided in the SAP about any computer simulations used to investigate the operating characteristics of complex clinical trial designs (such as adaptive designs); to choose between alternative outcome measures; or to determine sample size, accounting for the impact of noncompliance, missing data, subject eligibility criteria, etc. It is particularly important to discuss the range of conditions that were considered in the simulation and why this range was considered appropriate, how robust the findings were across the range of conditions considered, and how the study will adjust for any design deficiencies (e.g., bias, loss of power) the simulations revealed.

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.

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

Foreign Institutions

Foreign (non-U.S.) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions described throughout the SF424 (R&R) Application Guide.

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

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.

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.

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.

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.  

Applications Involving the NIH Intramural Research Program

The requests by NIH intramural scientists will be limited to the incremental costs required for participation. As such, these requests will not include any salary and related fringe benefits for career, career conditional or other Federal employees (civilian or uniformed service) with permanent appointments under existing position ceilings or any costs related to administrative or facilities support (equivalent to Facilities and Administrative or F&A costs). These costs may include salary for staff to be specifically hired under a temporary appointment for the project, consultant costs, equipment, supplies, travel, and other items typically listed under Other Expenses. Applicants should indicate the number of person-months devoted to the project, even if no funds are requested for salary and fringe benefits.

If selected, appropriate funding will be provided by the NIH Intramural Program. NIH intramural scientists will participate in this program as PDs/PIs in accord with the Terms and Conditions provided in this NOFO. Intellectual property will be managed in accord with established policy of the NIH in compliance with Executive Order 10096, as amended, 45 CFR Part 7; patent rights for inventions developed in NIH facilities are NIH property unless NIH waives its rights.

Should an extramural application include the collaboration with an intramural scientist, no funds for the support of the intramural scientist may be requested in the application. The intramural scientist may submit a separate request for intramural funding as described above.

Use of Common Data Elements in NIH-funded Research

Many NIH ICs encourage the use of common data elements (CDEs) in basic, clinical, and applied research, patient registries, and other human participants research to facilitate broader and more effective use of data and advance research across studies. CDEs are data elements that have been identified and defined for use in multiple data sets across different studies. Investigators are encouraged to consult the NIH CDE Repository and describe in their applications any use they will make of NIH-supported CDEs in their projects, when applicable. Use of CDEs can facilitate data sharing and standardization to improve data quality and enable data integration from multiple studies and sources, including electronic health records. NIH ICs have identified CDEs for many clinical domains (e.g., neurological diseases), types of studies (e.g. genome-wide association studies (GWAS)), types of outcomes (e.g., patient-reported outcomes), and patient registries (e.g., the Global Rare Diseases Patient Registry and Data Repository). NIH has established a “Common Data Element (CDE) Repository Resource Portal" (http://cde.nih.gov/) to assist investigators in identifying NIH-supported CDEs when developing protocols, case report forms, and other instruments for data collection. The Portal provides guidance about and access to NIH-supported CDE initiatives and other tools and resources for the appropriate use of CDEs and data standards in NIH-funded research.

NIH HEAL Initiative core Common Data Elements (CDE): The NIH HEAL Initiative research portfolio spans a broad array of data types that are a rich resource for future studies. Maximizing the value of data collected through the initiative is part of the initiative’s collective responsibility, given the magnitude of the opioid crisis and needs of individuals experiencing pain and addiction. To facilitate cross-study comparisons and improve the interpretability of findings, clinical pain research recipients collaborate and agree to use common data elements (CDE) for patient-reported outcomes (PROs). All HEAL studies collecting human subjects data and planning to use CDEs (even studies outside the clinical pain research portfolio) are strongly encouraged to search for applicable CDEs within the HEAL database, and use questionnaires from this database if possible. Studies using CDEs, regardless of whether they are part of the HEAL repository, will be required to report which questionnaires are being used. Details of HEAL CDEs can be found at https://heal.nih.gov/data/common-data-elements. HEAL pain clinical studies must include plan to use HEAL CDE (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 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 subjects are expected to use questionnaires by the HEAL CDE program, 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.

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.

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

Overall Impact

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

Scored Review Criteria

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

Significance

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

In addition, for applications involving clinical trials

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

For this NOFO:

• If accomplished,  how well will the rigorous data-driven and evidence-based mathematical/statistical/computational modeling goals  lead to significant advancements in the understanding of biological and/or psychosocial underpinnings of inter-individual differences, heterogeneity, and stratification of persons with lived pain experience?
• To what extent do the overall goals challenge existing paradigms, overcome long-standing roadblocks to progress, and/or develop in-depth understanding of the biological and/or psychosocial aspects of inter-individual differences in human pain conditions and co-morbid condition(s)?
• To what extentdoes the proposed research strategies and outcomes likely to impact effective management of human pain conditions and co-morbid conditions?
• To what extent does the application adequately describe whether prior research that serves as the key support for the proposed project employed rigorous practices such as minimization of potential experimenter biases, robust experimental designs, transparent reporting of results and analyses, and careful interpretation? How well does the application address ambiguity, weaknesses, or limitations in rigor of the prior research, if applicable?
• To what extent do the efforts described in the Plan for Enhancing Diverse Perspectives further the significance of the project? 

Investigator(s)

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

In addition, for applications involving clinical trials

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

For this NOFO:

• Based on the types and complexity of the research and data modeling activities proposed in this project, how well the proposed plan to include a variety of investigators with complementary scientific backgrounds/expertise will address the proposed scientific problem? 
• To what extent is each investigator necessary and will contribute to achieving the goals of the program? 
• To what extent do the PD/PI(s) and key personnel have the clinical, data handling and analytical/modeling expertise, experience, and ability to organize, manage and meet the proposed activities? 
•  
• If the application includes collaborating investigators who will not receive direct support, to what extent will these investigators participate in the program? If foreign investigators are involved, to what extent are they uniquely qualified to participate in the team?
• To what extent will the efforts described in the Plan for Enhancing Diverse Perspectives strengthen and enhance the expertise required for the project?

Innovation

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

In addition, for applications involving clinical trials

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

For this NOFO:

• To what extent the project involve innovative ideas and/or multidisciplinary approaches that would be very difficult to pursue through individually focused research grants on data collection vs development and validation of mathematical/statistical/computational models? 
• To what extent the project present strategies for innovative combinations of scientific fields, research approaches, data collection and analytical/modeling approaches & technologies, and/or intellectual viewpoints to address its goals?
• To what extent will the efforts described in the Plan for Enhancing Diverse Perspectives meaningfully contribute to innovation?

Approach

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

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

In addition, for applications involving clinical trials

Does the application adequately address the following, if applicable

Study Design

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

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

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

Data Management and Statistical Analysis

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

For this NOFO:

• To what extent does the proposed research strategy multidisciplinary and comprehensive on rigorous evidence-based modeling and understanding of inter-individual differences and/or heterogeneity of pain occurring with use of pain therapy/management, or a second pain condition, or a comorbid health condition, or a comorbid mental health condition, or opioid use / misuse, or alcohol use / misuse, or substance use / misuse conditions?
• Is the scientific rationale/premise of the study based on the clinical evidence on inter-individual differences in pain condition(s) and/or co-morbidities in relation to the focus of the project?
• How will the combination of scientific expertise (represented by the PD/PIs) and a multidisciplinary approach be transformative, and/or enable major advances in the biological and/or psychosocial understanding of inter-individual differences in human pain conditions and co-morbidities? 
• If new mathematical/statistical/computational models and/or databases or resource collections will be developed, are they well justified and clearly essential to the research goals? To what extent does the work plan make adequate use of existing institutional and/or regional resources?
• To what extent does the proposed research incorporate adequate methodological rigor where applicable, including, but not limited to, clear rationale for the chosen model(s) and primary/secondary endpoint(s), clear descriptions of tools and parameters, blinding, randomization, adequate sample size, pre-specified inclusion/exclusion criteria, appropriate handling of missing data and outliers, appropriate controls, preplanned analyses, and appropriate quantitative techniques?
• How well the applicant(s) clearly indicate the exploratory vs. confirmatory components of the study, consider study limitations, and plan for transparent reporting of all methods, analyses, and results so that other investigators can evaluate the quality of the work and potentially perform replications?
• Are the timeline and milestones associated with the Plan for Enhancing Diverse Perspectives well-developed and feasible?

Environment

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

In addition, for applications involving clinical trials

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

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

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

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

For this NOFO: 

To what extent will features of the environment described in the Plan for Enhancing Diverse Perspectives (e.g. collaborative arrangements, geographic diversity, institutional support) contribute to the success of the project?”

Additional Review Criteria

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

Study Timeline

Specific to applications involving clinical trials

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

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

Protections for Human Subjects

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

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

Inclusion of Women, Minorities, and Individuals Across the Lifespan

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

Vertebrate Animals

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

Biohazards

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

Resubmissions

For Resubmissions, the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project.

Renewals

Not Applicable

Revisions

Not Applicable

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

Applications from Foreign Organizations

Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.

Select Agent Research

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

Resource Sharing Plans

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

Authentication of Key Biological and/or Chemical Resources:

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

Budget and Period of Support

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

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by the Center for Scientific Review , 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 on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this NOFO. Following initial peer review, recommended applications will receive a second level of review by the 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.

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.

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 Assurance of Compliance form (HHS 690) in which the recipient agrees, as a condition of receiving the grant, to administer 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. 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.”

Not Applicable

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.

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.

HEAL Initiative Public Access and 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 follow all requirements and timelines developed through the HEAL Initiative Data Ecosystem (https://heal.nih.gov/about/heal-data-ecosystem), as described in HEAL’s compliance guidance (See “Already Funded” section: https://heal.nih.gov/data/complying-heal-data-sharing-policy):  

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

• Data generated by HEAL Initiative-funded projects must be submitted to study-appropriate, HEAL-compliant, data repositories to ensure the data is accessible via the HEAL Initiative Data Ecosystem. 
• Some repositories require use of specific data dictionaries or structured data elements, so knowing your repository’s requirements up front can help reduce the burden of preparing data for submission. 
• HEAL-funded recipients must follow requirements for selected repository.  

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

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

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

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

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

• At the completion of the study and/or when prepared to make the final data deposits in the repositor(ies) of choice, ensure your study registration (https://heal.github.io/platform-documentation/study-registration/) is complete. 
• 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, HEAL recipients are expected to integrate broad data sharing consent language into their informed consent forms.

Additional details, resources, and tools to assist with data related activities can be found at https://www.healdatafair.org/. 

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.

Recipients conducting research that includes collection of genomic data should incorporate requirements under the NIH Genomic Data Sharing Policy (NOT-OD-14-124, NOT-OD-15-086).

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.

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.

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].”

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 $25,000.  See the NIH Grants Policy Statement for additional information on this reporting requirement.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period.  The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS).  This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313).  As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available.  Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 and 2 CFR Part 200 – Award Term and Conditions for Recipient Integrity and Performance Matters.

Section VII. Agency Contacts

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

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

Finding Help Online: https://www.era.nih.gov/need-help (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-480-7075

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

D.P. Mohapatra, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9964
Email: dp.mohapatra@.nih.gov

Sarah Woller, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-1779
Email: sarah.woller@nih.gov

Melissa M Ghim, PhD
NIDCR - NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH
Phone: none
E-mail: ghimm@mail.nih.gov

Yu Lin, Ph.D.
NATIONAL INSTITUTE ON DRUG ABUSE (NIDA)
Phone: 301-435-1318
E-mail: ylin1@mail.nih.gov

Inna Belfer, MD, Ph.D.
National Center for Complementary and Integrative Health (NCCIH)
Phone: 301-435-1573
Email: inna.belfer@nih.gov

Yan Wang, MD, PhD
NIAMS - NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
Phone: 301-594-5032
E-mail: wangy1@mail.nih.gov

Rachel Altshuler, Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276-5873
Email: rachel.altshuler@nih.gov
 

Mark Egli, Ph.D.
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Phone: 301-594-6382
E-mail: megli@mail.nih.gov

Houmam H Araj
NEI - NATIONAL EYE INSTITUTE
Phone: (301) 435-8166
E-mail: ha50c@nih.gov

C. Brian Bai, Ph.D.
NHLBI - NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
Phone: 301-827-5212
E-mail: brian.bai@nih.gov

C. Brian Bai, Ph.D.

Devon Oskvig, Ph.D.
National Institute on Aging (NIA)
Phone: (301) 496-9350
E-mail: devon.oskvig@nih.gov

Susan Marden, PhD, RN
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-435-6838
Email: mardens@mail.nih.gov

Center for Scientific Review (CSR)
Email: FOAReviewContact@csr.nih.gov

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

Diana Rutberg, MBA
NIDCR - NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH
Phone: (301) 594-4798
E-mail: dr258t@nih.gov

Pamela G Fleming
NIDA - NATIONAL INSTITUTE ON DRUG ABUSE
Phone: 301-480-1159
E-mail: pfleming@mail.nih.gov

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

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

Sean Hine
National Cancer Institute (NCI)
Telephone: 240-276-6291
Email: hines@mail.nih.gov
 

Judy Fox
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Telephone: 301-443-4704
Email: judy.fox@nih.gov

 Karen Robinson Smith
NEI - NATIONAL EYE INSTITUTE
Phone: 301-435-8178
E-mail: kyr@nei.nih.gov

Nina Hall
NHLBI - NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
Phone: 301-301-827-2393
E-mail: hallnn@mail.nih.gov

Kathleen Moy
National Institute on Aging (NIA)
Phone: 301.827.2856
E-mail: kathleen.moy@nih.gov

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

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.