Department of Health and Human Services

Part 1. Overview Information

Participating Organization(s)

National Institutes of Health (NIH)

Components of Participating Organizations

National Center for Complementary and Integrative Health (NCCIH)

National Eye Institute (NEI)

National Heart, Lung, and Blood Institute (NHLBI)

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

National Institute on Drug Abuse (NIDA)

National Institute of Nursing Research (NINR)

National Institute on Minority Health and Health Disparities (NIMHD)

National Center for Advancing Translational Sciences (NCATS)

All applications to this funding opportunity announcement should fall within the mission of the Institutes/Centers. The following NIH Offices may co-fund applications assigned to those Institutes/Centers.

Office of Behavioral and Social Sciences Research (OBSSR)

Office of Research on Women's Health (ORWH)

Funding Opportunity Title
HEAL Initiative: Sickle Cell Disease Pain Management Trials Utilizing the Pain Management Effectiveness Research Network Cooperative Agreement (UG3/UH3, Clinical Trial Required)
Activity Code

UG3/UH3 Exploratory/Developmental Phased Award Cooperative Agreement

Announcement Type
New
Related Notices

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  • December 01, 2021 - NCCIH Announces Availability of Frequently Asked Questions (FAQs) for HEAL Sickle Cell Disease Pain Management Funding Opportunities RFA-AT-22-004 and RFA-AT-22-005. See Notice NOT-AT-22-006.
  • /ul>

Funding Opportunity Announcement (FOA) Number
RFA-AT-22-005
Companion Funding Opportunity
RFA-AT-22-004 , UG3/ UH3 Phase 1 Exploratory/Developmental Cooperative Agreement/Exploratory/Developmental Cooperative Agreement Phase II
Assistance Listing Number(s)
93.213, 93.846, 93.350, 93.867, 93.279, 93.313, 93.361, 93.837, 93.838, 93.839, 93.840, 93.233, 93.307
Funding Opportunity Purpose

The purpose of this Funding Opportunity Announcement (FOA) is to solicit cooperative agreement applications to support multisite effectiveness clinical trials of pharmacologic, nonpharmacologic, and/or multicomponent approaches for acute and/or chronic sickle cell disease (SCD) pain management, allowing continued opioid pain management as needed. However, opioid medication use alone should not be the only intervention studied. Trials supported under this initiative may also address the impact of these approaches on related psychological and functional outcomes to support improved overall well-being and quality of life. In addition, studies that address stigma, structural health care system, and social factors that may hinder quality comprehensive pain care for patients with SCD are also of interest. Investigators are encouraged to include the collection of well-justified biological markers or psychological processes that have demonstrated that they may mediate pain outcomes. Trials should collect sufficient measures to phenotype participants such as type of pain, variability of pain, co-occurring conditions, and social determinants of health. The studies must address questions within the mission and research interests of the NIH HEAL Initiative and evaluate preventive or treatment strategies or interventions including medications, biologics, procedures, medical and assistive devices and technologies, behavioral interventions, rehabilitation strategies, complementary interventions, integrated approaches, and delivery system strategies in well controlled trials in patients with SCD to manage acute and/or chronic pain.

The overall goal is to inform clinicians about the effectiveness of interventions such as coordinated, multidisciplinary management strategies that reduce acute and/or chronic SCD pain and that continue to provide access to opioid pain management as needed. Clinical trials will be conducted within the infrastructure of the HEAL Pain Management Effectiveness Research Network (HEAL ERN), which was established through the infrastructure of the National Center for Advancing Translation Sciences (NCATS) Trial Innovation Network (TIN) (www.trialinnovationnetwork.org).

Awards made under this FOA will support a milestone-driven planning phase (UG3) for 1 year, with possible transition to a clinical trial conduct phase (UH3) of up to an additional four years. Only UG3 projects that meet the scientific milestones and feasibility requirements will transition to the UH3 phase. The UG3/UH3 application must be submitted as a single application, following the instructions described in this FOA. This FOA may NOT be used for applications that propose testing of interventions to establish initial efficacy of drugs, devices or biologics for approval by the Food and Drug Administration (FDA).

Key Dates

Posted Date
October 29, 2021
Open Date (Earliest Submission Date)
November 15, 2021
Letter of Intent Due Date(s)

November 15, 2021

Application Due Dates Review and Award Cycles
New Renewal / Resubmission / Revision (as allowed) AIDS Scientific Merit Review Advisory Council Review Earliest Start Date
December 15, 2021 Not Applicable December 15, 2021 March 2022 May 2022 July 2022

All applications are due by 5:00 PM local time of applicant organization. All types of non-AIDS applications allowed for this funding opportunity announcement are due on the listed date(s).

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.

Expiration Date
December 16, 2021
Due Dates for E.O. 12372

Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide,except where instructed to do otherwise (in this FOA or in a Notice from NIH Guide for Grants and Contracts ).

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

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

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

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

  3. Use Grants.gov Workspace to prepare and submit your application and eRA Commons to track your application.


  4. Table of Contents

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

Purpose

The purpose of this Funding Opportunity Announcement (FOA) is to solicit cooperative agreement applications to support multisite effectiveness clinical trials of pharmacologic, nonpharmacologic, and/or multicomponent approaches for acute and/or chronic sickle cell disease (SCD) pain management, allowing continued opioid pain management when needed. However opioid medication use alone should not be the only intervention studied. Trials supported under this initiative may also address the impact of these approaches on related psychological and functional outcomes to support improved overall well-being and quality of life. In addition, studies that address stigma, structural health care system, and social factors that may hinder quality comprehensive pain care for patients with SCD are also of interest. Investigators are encouraged to include the collection of well-justified biological markers or psychological processes that have demonstrated that they may mediate pain outcomes. Trials should collect sufficient measures to phenotype participants such as type of pain, variability of pain, co-occurring conditions, and social determinants of health. The studies must address questions within the mission and research interests of the NIH HEAL Initiative and evaluate preventive or treatment strategies or interventions including medications, biologics, procedures, medical and assistive devices and technologies, behavioral interventions, rehabilitation strategies, complementary interventions, integrated approaches, and delivery system strategies in well controlled trials in patients with SCD to manage acute and/or chronic pain.

The overall goal is to inform clinicians about the effectiveness of interventions, such as coordinated, multidisciplinary management strategies that reduce acute and/or chronic SCD pain and that continue to provide access to opioid pain management as needed. Clinical trials will be conducted within the infrastructure of the HEAL Pain Management Effectiveness Research Network (HEAL ERN), which was established through the infrastructure of the National Center for Advancing Translation Sciences (NCATS) Trial Innovation Network (TIN) www.trialinnovationnetwork.org. Trials will be implemented at the Clinical and Translation Science Award (CTSA) Program hubs, which each may contain multiple clinical sites at different institutions, and/or any other clinical sites selected by the investigator that is not affiliated with the CTSA program.

Awards made under this FOA will support a milestone-driven planning phase (UG3) for 1 year, with possible transition to a clinical trial conduct phase (UH3) of up to an additional four years. Only UG3 projects that meet the scientific milestones and feasibility requirements will transition to the UH3 phase. The UG3/UH3 application must be submitted as a single application, following the instructions described in this FOA. This FOA may NOT be used for applications that propose testing of interventions to establish initial efficacy of drugs, devices or biologics for approval by the Food and Drug Administration (FDA).

Background

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

Sickle cell disease (SCD) is the most common inherited blood disorder in the United States, affecting up to 100,000 Americans, predominantly individuals of African descent and those who self-identify as Black (i.e., 1 in 365 African American children born with SCD) and individuals of Hispanic ethnicity (1 in 16,300). The most common complication of SCD is pain, including severe acute pain episodes primarily from vaso-occlusive crises, chronic persistent pain, and neuropathic pain. SCD pain symptoms span from childhood through adulthood and contribute to high rates of hospitalizations, emergency room visits, poor functional and psychosocial outcomes, and an increased rate of mortality. Management of acute and chronic pain among individuals with SCD is complex and often includes treatment such as opioid-based therapies which do not always address other co-occurring symptoms that may exacerbate pain, such as sleep disturbances, stress, anxiety, and depression. Even after curative SCD therapy, severe chronic pain continues for a significant proportion of individuals.

Further, the SCD population primarily comprises racial and ethnic minorities who experience disparities in receiving quality comprehensive care for SCD, including pain management. These disparities have been linked to the stigma associated with this disease as well as social factors such as racism and socioeconomic status. In turn this stigma associated with SCD impacts health outcomes, health seeking behavior, and patient-provider interactions. Indeed, recent reports from the National Academy of Sciences (https://www.nationalacademies.org/our-work/addressing-sickle-cell-disease-a-strategic-plan-and-blueprint-for-action#sectionPublications) and the Pain Management Best Practices Inter-Agency Task Force (https://www.hhs.gov/ash/advisory-committees/pain/reports/index.html) highlight the need for a paradigm shift to provide comprehensive care delivery models for managing pain and improving the overall well-being and quality of life of individuals with SCD associated pain. To address these combined challenges, a biopsychosocial approach to pain management that includes a multidisciplinary approach that addresses biological, psychological, and social influences on pain provides an opportunity to treat the whole person, improve overall health status, and possibly mitigate some of the factors leading to the stigma associated with SCD.

While opioid therapy remains vital for the current management of acute SCD pain, non-opioid pharmacologic and nonpharmacologic approaches for pain management have been deemed feasible and of interest to individuals with SCD. Research is needed to enhance the evidence base regarding the effectiveness of multicomponent non-opioid pharmacologic and nonpharmacologic approaches for acute and chronic SCD pain management to reduce different SCD pain types, improve related psychological and functional outcomes, and reduce reliance on solely opioid-based treatments.

In addition to scientific diversity, applicants should strive to incorporate diversity in their team development plan. Research shows that diverse teams working together and capitalizing on innovative ideas and distinct perspectives outperform homogenous teams. Scientists and trainees from diverse backgrounds and life experiences bring different perspectives, creativity, and individual enterprise to address complex scientific problems. There are many benefits that flow from a diverse NIH-supported scientific workforce, including: fostering scientific innovation, enhancing global competitiveness, contributing to robust learning environments, improving the quality of the research, advancing the likelihood that underserved or health disparity populations participate in, and benefit from health research, and enhancing public trust. Please refer to Notice of NIH's Interest in Diversity (NOT-OD-20-031) for more details.

Research Interests Specific to this FOA

This FOA is soliciting applications for clinical “effectiveness” research for management of acute and/or chronic SCD pain in ways that reduce the reliance solely on opioid-based treatments and to improve related psychological and functional outcomes. Effectiveness research is defined as the conduct and synthesis of research comparing the benefits and harms of different interventions and strategies to prevent, treat and monitor pain conditions in “real world” settings. The purpose of this research is to improve functional health outcomes by developing and disseminating evidence-based information to patients, clinicians, and other decision-makers, responding to their expressed needs, about which interventions are most effective for which patients under specific circumstances. To provide this information, comparative effectiveness pain research must assess a comprehensive array of health-related outcomes for diverse patient populations and subgroups.

Modified from Source: https://osp.od.nih.gov/wp-content/uploads/FCCCER-Report-to-the-President-and-Congress-2009.pdf

Research Objectives

This FOA solicits applications for UG3/UH3 exploratory/developmental phased award cooperative agreements to support multisite clinical trials to test the effectiveness of pharmacologic, nonpharmacologic, and/or multicomponent approaches for acute and/or chronic SCD pain management. Effectiveness trials may include or allow continuation of opioid medication use if appropriate, however opioid medication use alone should not be the only intervention studied. Trials supported in this initiative may also address the impact of these approaches on related psychological and functional outcomes to support improved overall well-being and quality of life. Trials may also address stigma, structural health care system, and social factors that may hinder quality comprehensive care. Applicants are encouraged to include participants across the lifespan including children, emerging adults, and adult populations, as appropriate. Clinical trials will be conducted within the HEAL ERN, utilizing the NCATS Trial Innovation Network infrastructure, which has dedicated pain and clinical trial design expertise. Multi-site trials will require participation of three or more clinical sites for completion of the study (e.g., in order to increase sample size, accelerate recruitment, or increase sample diversity and representation).

The following list provides examples of some of the potential research questions that might be addressed by trials supported by this FOA

  • Trials that evaluate options for the addition of pharmacologic, nonpharmacologic, and/or multicomponent approaches for acute and/or chronic SCD pain management which may reduce use of opioids;
  • Trials that examine pain management as well as impact on comorbidities such as sleep disturbance, anxiety, and stress;
  • Trials that evaluate the effectiveness of coordinated, multidisciplinary management strategies that reduce acute and/or chronic SCD pain and that continue to provide access to opioid pain management as needed;
  • Trials that support interventions to address social and structural barriers such as stigma and racial bias to improve SCD pain management care.

The research questions listed above are only examples, are not listed in priority order, and are not intended to be all inclusive.

IC-Specific Areas of Interest

National Center for Complementary and Integrative Health (NCCIH)

The NCCIH is interested in supporting comparative effectiveness trials that include complementary and integrative health approaches that have already demonstrated efficacy for SCD pain management. Complementary approaches include those with physical and/or psychological therapeutic inputs, often called mind and body approaches (e.g., acupuncture, yoga, tai chi, qi gong, meditation, hypnosis, music therapy, art therapy, spinal or chiropractic manipulation, and massage) as well as approaches with dietary or nutritional therapeutic inputs (e.g., special diets). Integrative approaches include therapies that combine complementary approaches with conventional medical interventions such as pharmacologic, surgery, or device-based treatments. NCCIH is also interested in applications that include multicomponent approaches that include a complementary approach to address pain outcomes as well as other related functional outcomes (e.g., anxiety, depression, stress, sleep disturbances) to promote a whole health approach to SCD pain management. Investigators may propose fully powered adaptive designs, such as sequential, multiple assignment, randomized trials (SMARTs) which are designed to determine the treatment options at decision points, possible tailoring variables, or a sequence of decision rules depending on the research question they seek to address. Investigators may also choose to use fully powered optimization designs if they fit their research question, such as a multiphase optimization strategy (MOST) design to determine how to optimize the intervention by evaluating which elements of a complex intervention are impactful. Applicants are encouraged to discuss applications with the NCCIH contact listed in Section VII. Agency Contacts.

National Heart, Lung, and Blood Institute (NHLBI)

The National Heart, Lung, and Blood Institute (NHLBI) provides global leadership in research, training, and education programs to promote the prevention and treatment of heart, lung, and blood diseases and sleep disorders (HLBS). The acute and chronic pain of sickle cell disease are major sources of decreased quality of life and are poorly responsive to current therapeutic modalities. Multi-site clinical trials that are of interest will evaluate the effectiveness of approaches that are informed by the bio-psychosocial model of pain management utilizing multi-disciplinary combinations of behavioral, pharmaceutical, interventional, and rehabilitative modalities to address the co-morbidities often present in patients with pain associated with SCD. While several studies have shown that the incidence of opioid addiction in SCD is low, the prolonged use of often high-dose daily oral opioid medications leads to dependence, risk of overdose, respiratory depression, immune dysfunction and hyperalgesia and has not been shown to be a highly effective treatment for chronic pain. Trials that evaluate the effectiveness of coordinated, multidisciplinary management strategies that reduce acute and/or chronic SCD pain and that, while continuing to provide access to opioid pain management when needed, can reduce or eliminate daily opioid use will also be of interest.

National Eye Institute (NEI)

Sickle cell disease can manifest in multiple ways including ophthalmic manifestations such as potential macular thinning, or peripheral retinal ischemia. The NEI is interested in applications that aim at reducing the burden of eye disease associated with sickle cell disease and/or improving patients' visual functioning.

National Institute on Drug Abuse (NIDA)

NIDA is interested in research to evaluate pain management interventions that may reduce the severity of opioid use disorders (OUDs) and overdose in patients with Sickle Cell Disease (SCD). These efforts include the evaluation of existing or new medications, behavioral treatments, or other interventions for pain management that can reduce the need for opioids, e.g., opioid-sparing, to treat pain conditions (simplified drug design, vaccine adjuvants, medication delivery). Additionally, research is encouraged that has the potential to reduce abuse liability of addictive pain treatments, and studies of pain medications, psychostimulants, anxiolytics, sedative/hypnotics that focus on clinical measurement of vulnerability to substance use disorder (SUD) in SCD. Research also is encouraged towards understanding the neurobiological bases (e.g., circuitry, neurochemical substrates) of the affective component of pain and how these overlap with neurobiological substrates of addiction. Understanding of acute and chronic pain processes; antinociceptive actions of opioids, cannabinoids, peptides; cellular processes of pain, analgesia, and tolerance (i.e., receptor internalization).

National Institute on Minority Health and Health Disparities (NIMHD)

The mission of NIMHD is to lead, conduct and support scientific research to improve minority health and reduce health disparities in the populations that include Blacks/African Americans, Hispanics/Latinos, American Indians/Alaska Natives, Asian Americans, Native Hawaiians and other Pacific Islanders, socioeconomically disadvantaged populations, underserved rural populations, immigrant populations and sexual and gender minorities. In the context of this FOA, NIMHD is particularly interested in encouraging applications that include, but are not limited to: address the intersection of acute and chronic pain management in SCD and ways to maintain continuity of care in patients with acute and chronic pain, and multilevel strategies to improve services for SCD, strategies to address social determinants of health for improving health and reducing health disparities; research on the outcomes of implementation, management and treatment of acute and chronic pain in SCD; conduct subpopulation analysis to determine which interventions work best for specific minority and underserved population groups with the intent to focus on improving quality of life. We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

National Institute of Nursing Research (NINR)

The National Institute of Nursing Research (NINR) supports research that uses nursing’s holistic perspective to improve individual and population health outcomes and eliminate health inequities by bridging biomedical science and provision of healthcare services with the realities of people’s lives and living conditions (i.e., social determinants) across the clinical and community settings where nurses practice. NINR encourages research that integrates factors at multiple levels to identify their role in health, health improvement and health inequities with the goal of improving the health of individuals, families, and populations.

In the context of this FOA, NINR’s interests include but are not limited to the following topics:

• Studies of SCD pain management that address SCD health-related social risk factors and social needs within the context of clinical practice and health care delivery

• Research that addresses stigma, access to quality care, bias, and structural barriers impacting health outcomes, health seeking behavior, and patient-provider interactions

• Projects aimed at under-served, uninsured, and under-insured SCD populations

• Trials that include efforts to identify and eliminate negative effects of implicit bias in healthcare providers

• Multidisciplinary, multi-level interventions or multi-component delivery models that engage the SCD community

Office of Research on Women’s Health (ORWH)

The Office of Research on Women's Health (ORWH) is part of the Office of the Director of NIH and works in partnership with the 27 NIH Institutes and Centers to ensure that women's health research is part of the scientific framework at the NIH and throughout the scientific community.

Sickle cell disease (SCD) is the most common inherited blood disorder in the United States. The most common complication of SCD is pain, including severe acute pain, chronic persistent pain, and neuropathic pain. Given the higher prevalence of pain disorders in females and their greater pain sensitivity, it is crucial to include women in pain and pain-management research.

For the purposes of this FOA, ORWH also supports research on SCD pain and the intersectionality of sex, gender, race, and biopsychosocial and cultural factors throughout the lifespan that affect health of both women and men.

Integrating the purposeful accounting for sex as a biological variable (SABV) in biomedical research on SCD pain and pain management will fill gaps in our knowledge and inform more effective, personalized approaches to improve health for women and men. The 2019-2023 Trans-NIH Strategic Plan for the Health of Women is available on the ORWH website for additional guidance.

It is expected that the effectiveness trials in the HEAL ERN will recruit women in sufficient numbers to determine sex-specific responses as well as sex differences in trial outcomes. These comparisons have significant clinical relevance given the higher prevalence of pain in women. Studies should, as appropriate, enroll both sexes to better understand the influence of sex as a variable.

Applicants should review the NIH HEAL website at https://heal.nih.gov/funding/awarded and the Patient-Centered Outcomes Research Institute website https://www.pcori.org/research-results https://www.pcori.org/research-results to avoid submitting a trial that overlaps significantly with other on-going trials testing methods to manage pain.

This FOA may NOT be used for applications that propose testing of interventions to establish initial efficacy of drugs, devices or biologics for approval by the FDA (see instead other opportunities such as EPPIC-Net below). Applicants interested in conducting such trials are encouraged to contact an NIH Program Official of the scientifically appropriate NIH Institute or Center to discuss other FOAs for this purpose. Non-responsive applications will be withdrawn without review.

Opportunities to Submit other Types of Pain Clinical Trials:

For further information on these programs see: https://www.painconsortium.nih.gov/Funding_Research/Funding_Opportunities

The Early Phase Pain Investigation Clinical Network (EPPIC-Net) will provide infrastructure for the rapid design and performance of high-quality Phase 2 clinical trials to test promising novel therapeutics for pain. This network will support exploratory clinical trials of investigational drugs and biologics, investigational devices, natural products, and surgical procedures for the treatment of pain. These trials may include deep phenotyping, validation of biomarkers and proof of mechanism, to support justification and provide the data for designing a future Phase 3 trial. The specific pain conditions of interest for EPPIC-Net include well-defined conditions with high unmet therapeutic needs in patients across the lifespan. Further information can be found at HEAL Initiative: EPPIC-Net Pain Research Asset Application (OT2) (nih.gov) (OTA-21-005).

The Pragmatic and Implementation Studies for the Management of Sickle Cell Disease Pain (PRISM-SCD; RFA-AT-22-004) program will support embedded pragmatic or implementation trials to inform the uptake of pharmacologic, nonpharmacologic, and/or multicomponent approaches for acute and/or chronic SDD pain management in health care systems that serve the SCD population. The program requires that the intervention under study be embedded into health care delivery system, real world settings. The pragmatic trial model collects most data needed for analysis of the research question as part of clinical care, and it is expected that this data will be obtained primarily through the electronic records of the health care system. Clinical trials will be conducted within the infrastructure of the HEAL PRISM Program Coordinating Center.

Overview of the HEAL ERN Network

Recipientswill be required to conduct their studies through the NIH HEAL ERN which has dedicated pain and clinical trial design expertise. The HEAL ERN will use the infrastructure of the NCATS Trial Innovation Network (TIN) (www.trialinnovationnetwork.org) to provide scientific guidance and coordination of the HEAL ERN trials. The TIN works with the broad consortium of Clinical and Translational Science Awards (CTSA) hubs (https://ctsa.ncats.nih.gov/) that each may contain multiple clinical sites at different institutions, to implement studies. Points of contact (POC) for the HEAL ERN at the individual CTSA hubs will be posted on www.trialinnovationnetwork.org www.trialinnovationnetwork.org. TIN dedicated pain and trial experts will participate on study teams of awarded UG3/UH3 projects during the planning and implementation phases and will provide clinical coordination center (CCC) services, data coordination center (DCC) services, recruitment and retention services, and biostatistical support for the UH3 trials.

The HEAL Pain Management Clinical Effectiveness Research Program Overview

Pain experts and clinical trial experts from the HEAL ERN CCC, DCC, Recruitment Center and Biostatistics core, NIH staff, and the awardees investigative team (PIs, biostatistician and study coordinator) will serve as the Clinical Trial Steering Committee, one for each trial, and will work collaboratively to plan and implement the trials. A consortium of all the Clinical Trial Steering Committees across all funded trials – defined here as the Program Steering Committee - will convene yearly in person or by conference call. The individual Clinical Trial Steering Committees will meet regularly throughout the duration of the implementation phase of the trials.

Specific functions provided by the HEAL ERN CCC, DCC, Recruitment Center and Biostatistical core include:

  • Developing the final study protocol with the study team investigators.
  • Providing study design support and independent statistical analysis of the primary trial results; and interpretation of results for manuscripts and publications.
  • Finalizing recruitment and retention plans with the site investigators before initiation of the trial;
  • Developing associated trial documents, including the Manual of Procedure or Standard Operating Procedures; materials for site investigators, case report forms and training materials for study personnel with the study team.
  • Training clinical site investigators and staff for the individual trials. Training areas include, but are not limited to, regulatory requirements, Good Clinical Practice (GCP), adverse event reporting, human subject protections, informed consent, and NIH policies and procedures;
  • Developing and maintaining a data management system for trial data collection and storage and adverse event reporting.
  • Providing randomization support.
  • Providing clinical operations and monitoring support including project management, to oversee and coordinate activities associated with the clinical trials, study implementation, from study start-up through additional site selection as needed, enrollment, site management, study monitoring and close out. This includes assistance finding additional sites if needed in the UG3 and UH3 phase to meet enrollment goals.
  • Monitoring enrollment and retention at the individual sites and working with sites that fail to meet their enrollment targets.
  • Preparing reports for the Data and Safety Monitoring Boards.
  • Providing single IRB services for the trial.
  • Working with the awardees to execute the Master Clinical Trial Agreement to the individual clinical sites, and
  • Providing logistics for face to face-to-face meetings of the cooperatives’ investigators.

Applicants should make note of the following:

Applicants should propose their primary outcome based on what is most appropriate for the trial question. Standardized pain measures and functional outcomes are strongly encouraged to ensure that data is translatable across all HEAL initiative pain studies. Secondary outcomes, including selected patient reported psychological and functional outcomes related to pain, opioid use and selected pain and associated measures, will be added to the protocol during the UG3 development phase. A final list of these required measures will be developed during the FY2022 planning year collaboratively by the Clinical Trial Steering Committee and additional experts as appropriate.

The award and continuation of funding are subject to milestones to be specified in the notice of grant award. At the time of an award, the PD(s)/PI(s), TIN personnel, and NIH staff will negotiate the scope and study development activity timeline for UG3 award and implementation activity timeline for the UH3 award. The project work scope and timeline will include identifying the primary individual or entity and other contributors responsible for study development, start-up and implementation activities, and the timeline for completion of these activities.

Applications that do not include milestones will be considered non-responsive to this FOA and will not be reviewed (see section below: Milestones and UG3/UH3 Transition)

NIH is developing guidance for collection of common data elements and data harmonization across HEAL and HEAL related clinical pain studies. The guidance is applicable to this FOA.

Applicants should include letters of intent to participate from sites named in the application, whether they be within and outside the CTSA consortium.

NIH Resources: As appropriate, applicants are encouraged to make use of the following resources for clinical research including:

(a) Clinical and Translational Science Award (CTSA) program (https://nacts.nih.gov/ctsa);

(b) NIH Toolbox (http://www.nihtoolbox.org);

(c) PROMIS (http://www.nihpromis.org); and

(d) NINDS Common Data Elements (http://www.commondataelements.ninds.nih.gov).

(e) PhenX Social Determinants of Health (SDOH) Assessments Collection (https://www.phenxtoolkit.org/)

Scope of the UG3/UH3 FOA

Each UG3/UH3 Clinical Trial Implementation Cooperative Agreement application can propose the planning and implementation of only one clinical trial.

NIH is interested in supporting clinical trials that are designed to answer questions based on a strong scientific premise and are carried out through a robust approach. To adequately plan and finalize the details for implementation of the clinical trials, investigators, in coordination with the CCC and DCC, and NIH staff, need time to prepare. Therefore, the UG3 component of the award will support a one-year planning phase during which limited funds will be awarded. Applicants and recipients of UG3 funding should note that the UG3 award does not guarantee subsequent UH3 funding for implementation of the clinical trial. Only those trials that successfully meet the scientific milestones and feasibility requirements for transition will be funded to move to the trial implementation phase (UH3).

Clinical Trial Planning Phase (UG3)

The UG3 award supports the planning period and is not intended for the collection of preliminary data (neither clinical nor pre-clinical studies) about the efficacy or effectiveness of an intervention, or the collection of prospective data to support the rationale for a clinical trial. During this year, the awardees, as part of the Clinical Trial Steering Committee will develop their protocols and associated study documents.

After awards are made, the recipientswill assess and refine the study design and statistical analysis collaboratively through the Clinical Trial Steering Committee. NIH Program staff will ensure that sets of common data elements are collected and used appropriately in the studies to ensure translation of shared data across HEAL supported clinical studies.

Examples of study documents that will be developed with the TIN CCC, DCC and biostatistical core during the UG3 phase include, but are not limited to:

  • A final clinical protocol developed in cooperation with the CCC, DCC and biostatistical core following International Conference on Harmonization (ICH) E6 Good Clinical Practice Consolidated Guidance, prepared using the standard interventional protocol template that will provided by the HEAL ERN.
  • The Manual of Procedures (MOP), developed in collaboration with the HEAL ERN DCC and study site investigators including a detailed description of study procedures and process details.
  • Staff training and recruitment plans in collaboration with the CCC and Recruitment Innovation Center.
  • The final statistical analysis plan, which will be developed in collaboration with the HEAL ERN biostatistical core.
  • The electronic data capture system, that will be developed and maintained by the TIN DCC as the central HEAL ERN data capture system.
  • The consent form(s) or, if applicable, permission and assent form(s), which will be developed with assistance from the HEAL ERN CCC and DCC.
  • Safety standards and regulatory processes.
  • Plans for biospecimen collection (if appropriate to the study) and storage protocols;
  • A plan for the administration of study agent(s), if applicable.
  • Detailed description of Roles and Responsibilities of study personnel developed in conjunction with the HEAL ERN CCC.
  • The final quality management and data management plans developed with the HEAL ERN CCC and DCC; and
  • Strategies to put in place should enrollment or retention not meet specified metrics.

The final protocol must be accepted by NIH and receive approval by the single IRB and the Data and Safety Monitoring Boards (DSMBs) overseeing the individual trials. In addition, each site must agree to use a Master Clinical Trial Agreement that will be provided by the HEAL ERN CCC, which serves as a one-time contract for participation in a HEAL ERN study and are expected to use a single Institutional Review Board (sIRB).

Clinical Trial Implementation Phase (UH3):

The planning year will be followed by up to four additional years of higher funding levels, during which the study will be implemented. The objective of the up to 4-year UH3 implementation phase is to conduct the clinical trial in accordance with activities planned in the UG3 phase. The trial outcome measure(s) must be clinically meaningful and important to stakeholders including patients and health care providers. The NIH expects clinical trials supported during the UH3 phase to be hypothesis driven, milestone-defined, and have the potential for high impact within the research mission of the HEAL Pain initiative. The clinical trial must meet all applicable NIH, Food and Drug Administration (FDA), and Office of Human Research Protections (OHRP) policy requirements.

Milestones and UG3/UH3 Transition

Applications must include well-defined milestones for the planning phase (UG3) and annual milestones for the clinical trial implementation phase (UH3). Prior to a pending award, the PD/PI and NIH will negotiate a final list of milestones for each year of support. The proposed milestones for the UH3 phase may be revised during the award period in coordination with NIH staff, the CCC and DCC, as activities in the UG3 phase progress.

At the completion of the UG3 planning phase or sooner if possible, the applicant will be required to submit a detailed transition proposal for the UH3 clinical trial implementation phase. The UH3 transition proposal will undergo an administrative review to determine whether the study will be awarded the implementation phase (UH3). The review will determine if the UG3 planning milestones named in the “Milestone Plan” have been met, and that the UH3 phase can successfully test the chosen hypothesis in a timely fashion.

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 awardees 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.

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

Section II. Award Information

Funding Instrument

Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH scientific or program staff will assist, guide, coordinate, or participate in project activities. See Section VI.2 for additional information about the substantial involvement for this FOA.

Application Types Allowed
New

The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types. Only those application types listed here are allowed for this FOA.

Clinical Trial?

Required: Only accepting applications that propose clinical trial(s).

Need help determining whether you are doing a clinical trial?

Funds Available and Anticipated Number of Awards

The NIH HEAL Initiative expects to commit $1,500,000 direct costs in FY 2022 to fund approximately 3 awards through this FOA and the companion FOA, RFA-AT-22-004, pending availability of funds and receipt of a sufficient number of meritorious applications.

Award Budget

The application budget for the UG3 phase is limited to $500,000/year in direct costs. Costs for each year of the UH3 phase are limited to $1 million/year in direct costs. The Trial Innovation Network will provide infrastructure including the data management system, clinical coordination, and monitoring. These trial infrastructure costs should not be included in the UG3/UH3 budgets.

Award Project Period

The UG3 phase is limited to up to one year and the UH3 phase can request up to four years of support. The total project period for an application submitted in response to this FOA may not exceed 5 years.

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

Section III. Eligibility Information

1. Eligible Applicants

Eligible Organizations

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Local Governments

  • State Governments
  • County Governments
  • City or Township Governments
  • Special District Governments
  • Indian/Native American Tribal Governments (Federally Recognized)
  • Indian/Native American Tribal Governments (Other than Federally Recognized)

Federal Governments

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

Other

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

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

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

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

Required Registrations

Applicant organizations

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

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

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

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

Eligible Individuals (Program Director/Principal Investigator)

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 his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

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

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

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

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide except where instructed in this funding opportunity announcement 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:

Martina Schmidt, Ph.D.
Telephone: 301-594-3456
Email:SchmidMa@mail.nih.gov

Page Limitations

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

Instructions for Application Submission

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

SF424(R&R) Cover

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

SF424(R&R) Project/Performance Site Locations

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

SF424(R&R) Other Project Information

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

SF424(R&R) Senior/Key Person Profile

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

R&R Budget

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

Costs not to include:

The budget should not contain costs for Clinical Coordinating Center, the Data Coordinating Center or a data management system. These will be supplied through core funding.

Costs for single IRB review will be supplied through core funding if the applicant uses a Trial Innovation Network single IRB.

Costs to include:

  • Costs to clinical sites for screening, enrollment and evaluation of participants or costs such as core laboratory costs, biospecimen shipping costs or costs for acquiring study agents should be included in the applicant’s budget as study costs.
  • Costs at the clinical sites, budgeted on a per-subject or per-procedure basis. Applicants should provide a breakdown of the total per subject costs as part of the budget justification and should indicate how the cost for an item or procedure was determined.
  • Costs for collection, analysis, storage, and shipping of biospecimens during the study duration should be included as a separate item in the budget. Specimens collected beyond those needed for the study or remaining at the close of study will be shipped and stored in the NIH HEAL common repository. Applicants are encouraged to provide specimens to the central HEAL repository for future access. Costs for shipping to the repository should be included in the budget. Costs for long-term storage in the HEAL repository will be covered through other HEAL funds.
  • Applicants should budget for the investigator team to travel to a face to face annual one-day, in-person-within study investigator meeting, and applicants should budget to allow up to 6 persons from the investigator team to attend. (The expenses of the meeting room rental will be covered by NIH.) If some trial costs are to be borne by sources other than NIH, these contributions must be presented in detail in the budget justification. These costs borne by third parties do not constitute cost-sharing as defined in the current NIH Grants Policy Statement and should not be presented as part of the requested budget.

R&R Subaward Budget

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

PHS 398 Cover Page Supplement

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

PHS 398 Research Plan

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

Significance and Clinical Relevance: Describe the significance of the proposed effectiveness clinical trial in the context of establishing the benefits of non-pharmacologic, pharmacologic, multicomponent or device interventions for pain management and the risks and benefits of the proposed study interventions. Discuss how the trial will test the hypotheses proposed and how the results of the trial (positive or negative) will advance the field and inform guidelines. Applicants are encouraged to include evidence such as letters or references that relevant stakeholders (e.g., potential subjects, referring and treating physicians, patient organizations, or professional organizations) view the question to be important.

Previous Studies: Present the major findings of the previous efficacy clinical studies that led to the proposed effectiveness trial. Ensure that the data supporting the proposed trial meet the NIH scientific rigor guidelines (see https://grants.nih.gov/grants/guide/notice-files/NOT-OD-15-103.html). Data supporting efficacy of the proposed intervention may come from the applicant’s previous work or from published literature.

Investigator(s): Describe the expertise of the study team in the conduct of multi-center trials, the team’s ability to plan and implement the proposed study, and the investigator’s experience working cooperatively with a consortium that includes a central CCC and DCC without duplicating information in the biosketches.

Approach:

The approach should clearly justify the clinical relevance for the length of observation for the pain outcome and the additional outcomes such as adverse effects associated with treatment. Do not duplicate information described in the Study Record: PHS Human Subjects and Clinical Trials Information form.

The Approach section should have a clear demarcation of the UG3 and UH3 portions of the application.

For the UG3 phase:

  • Describe the study development activities outlined in the UG3 Milestone Plan in the PHS Human Subjects and Clinical Trials Information Form planned for the UG3 phase, including a plan to meet the milestones.

For the UH3 phase, include the following:

  • An assessment of the feasibility of recruiting participants who are eligible for the proposed research.
  • An overview of the proposed study design that must justify the selected trial elements provided in the Protocol Synopsis, including:
  • Rationale for the selected trial design and allocation method.
  • Rationale for selection of the intervention to be tested and a description of how and at what dosing and/or frequency the intervention will be administered.
  • Justification for selection of the primary and secondary outcome measures and a description of how the outcome variables will be collected and the criteria for measuring the outcomes. Applicants should allow flexibility in determining the secondary outcome measures pending NIH determinations of Common Data Elements for this particular study.
  • Description of the study population, including the pain condition or pain state, sample size, pertinent demographic information, required health status, and geographic location. Justify why the study population is an appropriate group to address the study objectives. Do not duplicate information described in Section 2 (Study Population Characteristics) of the Study Record: PHS Human Subjects and Clinical Trials Information form.
  • Discuss potential biases or challenges in the proposed trial and how they will be minimized and/or addressed.
  • Describe the study activities outlined in the UH3 Milestone Plan in the PHS Human Subjects and Clinical Trials Information Form and how the milestones will be met.

Letters of Support

For-profit applicants must include a letter(s) of support confirming that the required secured cost matching (cash; in-kind commitments such as salary, consultant costs, equipment) is available and confirm that the essential personnel have the authority within the organization to allocate resources.

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.

The following modifications also apply:

.

HEAL Data Sharing

NIH intends to maximize the impact of HEAL Initiative-supported projects through broad and rapid data sharing. Consistent with the HEAL Initiative Public Access and Data Sharing Policy (https://heal.nih.gov/about/public-access-data), all applications, regardless of the amount of direct costs requested for any one year, are required to include a Data Management and Sharing Plan outlining how scientific data and any accompanying metadata will be managed and shared. The plan should describe data types, file formats, submission timelines, and standards used in collecting or processing the data. It is expected that data generated by HEAL Initiative-funded projects will be submitted to study-appropriate domain-specific or generalist repositories in consultation with the HEAL Data Stewardship Group to ensure the data is accessible via the HEAL Initiative Data Ecosystem.

To maximize discoverability and value of HEAL datasets and studies, and facilitate data integration and collaboration, applications submitted in response to this FOA 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.

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)
  • NIH encourages researchers to explore the use of the HL7 FHIR® (Fast Healthcare Interoperability Resources) standard to capture, integrate, and exchange clinical data for research purposes and to enhance capabilities to share research data (NOT-OD-19-122). The FHIR® standard may be particularly useful in facilitating 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.

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).

Appendix:

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

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

PHS Human Subjects and Clinical Trials Information

When involving human subjects research, clinical research, and/or NIH-defined clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

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

Study Record: PHS Human Subjects and Clinical Trials Information

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

Section 2 - Study Population Characteristics

2.5 Recruitment and Retention Plan

Applicants should state how many sites will be needed and survey the potential clinical sites to ensure that recruitment targets can be met.

Include a description of how additional sites not named in the application (Clinical and Translational Science award (CTSA) Program hubs sites or any other investigator-selected sites) will be selected and used as clinical sites to implement the trial. Specify the criteria for selecting additional sites. Existing other network clinical sites suitable to answer the study question may also be used, but the other network must use the TIN DCC and CCC and participate in all HEAL ERN activities.

The plan should also include a contingency plan for adding new sites if enrollment falls behind targets or discontinuing enrollment of new participants at sites that do not meet individual goals.

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

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

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

Section 3 - Protection and Monitoring Plans

3.2 Single Institutional Review Board (sIRB)

Awardees must use a single Institutional Review Board (sIRB) to conduct the ethical review required by HHS regulations for the Protections of Human Subjects Research unless review by the proposed sIRB would be prohibited by a federal, tribal, or state law.. For this FOA, the three Trial Innovation Network (TIN) Single IRBs are available to serve as the sIRB of record. If the awardee elects to use these sIRBs, the assignment will be made post award. There is no need to request the services. For more information about the Single IRBs affiliated with the TIN, see

https://trialinnovationnetwork.org/elements/central-irb/

3.3 Data and Safety Monitoring Plan

It is expected that a Data and Safety Monitoring Board (DSMB) will oversee each trial, consistent with the policy of the IC managing the trial. Applicants should refer to the specific guidelines of the Institute or Center with a scientific interest in the proposed trial to guide development of their Data and Safety Monitoring Plan (DSMP). The final DSMP will be developed with the managing IC after award. For IC specific DSMB policies see https://www.painconsortium.nih.gov/Funding_Research/Funding_Opportunities

A Clinical Site Monitoring Plan will be developed with the Clinical Trial Steering Committee during the first year of the study. This plan will include how site adherence to the protocol and consenting process will be ensured, who is responsible for site monitoring, the frequency of planned monitoring activities and the plan for handling deficiencies, or closure of sites. Plans for training and, if needed, certifying site personnel to complete study procedures will be developed by the PD/PI and HEAL ERN DCC and CCC during the UG3 phase of the study.

A detailed Data Management Plan, including the methods and systems for data collection and quality control, and for ensuring data confidentiality and privacy, and the process for locking the final dataset will be developed by the HEAL ERN DCC and the PD/PI during the UG3 phase of the study.

Describe the plans, if any, to use non-traditional data collection approaches (e.g., digital/mobile/sensor technologies and web-based systems) and why these are appropriate.

Section 4 - Protocol Synopsis

4.3 Statistical Design and Power

Applicants should provide a Statistical Analysis Plan (SAP) including details about the power analysis used to determine how the study sample size was determined, analyses specified in the study protocol, including a description of how the statistical analysis of the primary, secondary and other endpoints will be performed, how missing data will be handled, plans for interim analyses for safety and futility, plans for recalculation of the sample size midway through the trial (if applicable), etc.

The final SAP will be developed with statisticians from the TIN biostatistics core. There must be a plan for an independent biostatistician to analyze study results according to the prespecified statistical analysis plan.

4.5 Will the study use an FDA-regulated intervention?

This FOA will not support studies of interventions of investigational products under IND or IDE.

4.7 Dissemination Plan

UG3/UH3 applicants must submit a plan for the dissemination of NIH-funded clinical trial information that will address how the expectations of the NIH Policy on the Dissemination of NIH-funded Clinical Trial Information will be met. Responsibility for adhering to this policy lies with the UG3/UH3 grantee institution, not with the TIN Coordinating Center awardees.

Section 5 - Other Clinical Trial-Related Attachments

5.1 Other Clinical Trial-related Attachments

Additional Instructions: The information provided here will be considered by reviewers and is meant to supplement, not duplicate, information provided in the Research Plan or other sections of the PHS Human Subjects and Clinical Trials Information form. All attachments listed below must be provided or the application will not be peer reviewed. The following documents must be uploaded as separate pdf files with the names indicated below.

1. Schedule of Events.

The filename "Schedule of Events" should be used to name this attachment. If multiple attachments are needed, amend the file name accordingly (e.g., Schedule of Events 1, Schedule of Events 2, etc.). Provide a schematic, table, or text description of the protocol-specified schedule of events for an individual study participant. It should capture each study visit/assessment time point and planned activity(ies) for each time point.

2. Milestone Plan.

The filename "Milestone Plan" should be used to name this attachment. If multiple attachments are needed, amend the file name accordingly (e.g., Milestone Plan 1, Milestone Plan 2, etc.).

The Milestone Plan must describe separate milestones for the UG3 and UH3 phases.

Applicants are required to provide detailed project performance and timeline objectives. This attachment must include two sections: those milestones to be completed during the UG3 planning phase and those to be completed during the UH3 phase. The plan should present an overview of the project timeline to achieve the following general milestones, as applicable:

Milestones to be completed during the UG3 phase:

  • Finalization of plans to obtain study agent(s), if applicable;
  • Finalization of clinical sites, demonstration that the necessary study population is available at the clinical sites, and finalization of plans to add or drop clinical sites if needed;
  • Finalization of agreements for use of resources available within CTSAs, practice-based research networks, patient registries, etc.;
  • Finalization of clinical protocol;
  • Regulatory approvals (IRB and applicable oversight committees);
  • Finalization of all documents necessary to implement the trial, such as case report forms;
  • Registration of clinical trial in ClinicalTrials.gov; and
  • Participation in consortium and common data elements process.

Milestones to be completed during the UH3 phase:

  • Site activation;
  • Enrollment of the first subject;
  • Enrollment and randomization, if applicable, of 25%, 50%, 75% and 100% of the projected study population;
  • Any planned interim analyses;
  • Completion of data collection time period;
  • Completion of primary endpoint and secondary endpoint data analyses;
  • Completion of final study report; and
  • Reporting of results in ClinicalTrials.gov per the NIH policy on Dissemination of NIH-Funded Clinical Trial Information.
  • Milestones and timelines will be refined and finalized in consultation with Program staff at the time of award

Applications that lack the Milestone Plan attachment are considered nonresponsive and will not be reviewed.

Delayed Onset Study

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

PHS Assignment Request Form

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

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

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

4. Submission Dates and Times

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

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

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

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

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

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

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

7. Other Submission Requirements and Information

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

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

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

Important reminders:

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

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

See more tips for avoiding common errors.

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

In order to expedite review, applicants are requested to notify Dr. Martina Schmidt in the NCCIH Referral Office by email at SchmidMa@mail.nih.gov when the application has been submitted. Please include the FOA number and title, PD/PI name, and title of the application.

 

Post Submission Materials

Applicants are required to follow the instructions for post-submission materials, as described in the policy. Any instructions provided here are in addition to the instructions in the policy.

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

  • Updated Milestones Plan (e.g., due to the hiring, replacement, or loss of an investigator; change to clinical sites)

Section V. Application Review Information

1. Criteria

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

For this particular announcement, note the following: This FOA includes Additional Review Criteria on Milestones, which require comment by reviewers and which are to be considered when determining the overall impact score.

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

Overall Impact

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

Scored Review Criteria

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

 

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

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

Specific to this FOA:

Does the application provide evidence that relevant stakeholders (e.g., potential participants, referring and treating physicians, patient groups) view the question to be important? Is there evidence that the trial is powered to detect a change in pain or function that is meaningful to patients with SCD?

Is there adequate data supporting efficacy of the proposed intervention to warrant an effectiveness trial for the selected outcome(s) in the proposed population?

Are the results from the proposed trial likely to inform evidence-based guidelines for management of acute and/or chronic SCD pain in ways that reduce the reliance solely on opioid-based treatments to improve related psychological and functional outcomes? If applicable, would the study impact improve stigma, structural health care system, and social factors that may hinder quality comprehensive pain care for patients with SCD?

 

 

 

 

 

 

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

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

 

 

 

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

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

 

 

 

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?

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

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

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

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

Specific to this FOA:

If applicable, are there clear plans to obtain any study agents? Are there clear plans to work in collaboration with the DCC and CCC for developing a final clinical protocol and associated documents in the UG3 phase? Are there appropriate plans for the final selection of the clinical sites and necessary populations for the future UH3 phase study? Is there an adequate discussion of potential challenges that are anticipated during planning and study implementation, and how they will be addressed? Is there evidence of how the investigators will work with the consortium to finalize the UH3 study plans? Is the plan appropriate? Are pain outcomes from participants collected for a time period that is clinically meaningful to inform clinical decision making?

How well does the application address the requirements of the HEAL Data Sharing Plan?

 

 

 

 

 

 

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

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

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

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

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

 

 

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.

 

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)?

 

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.

 

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.

 

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

 

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.

 

Not Applicable.

 

Not Applicable.

 

Not Applicable.

 

Are the steps and milestones clearly defined? Are the milestones feasible, well developed and quantifiable with regard to specific goals and accomplishments? Are adequate criteria provided for the UG3 phase that will be utilized in determining milestone completion before proceeding to the next phase of the project? Are the UH3 milestones appropriate for the next phase of the project?

Additional Review Considerations

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.

 

Not Applicable.

 

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).

 

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: (1) 2) Genomic Data Sharing Plan (GDS).

 

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.

 

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

2. Review and Selection Process

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

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 FOA.

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 FOA. Following initial peer review, recommended applications will receive a second level of review by the National Advisory Council for Complementary and Integrative Health (NACCIH). 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 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 FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website.  This includes any recent legislation and policy applicable to awards that is highlighted on this website.

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

ClinicalTrials.gov: If an award provides for one or more clinical trials. By law (Title VIII, Section 801 of Public Law 110-85), the "responsible party" must register and submit results information for certain “applicable clinical trials” on the ClinicalTrials.gov Protocol Registration and Results System Information Website (https://register.clinicaltrials.gov). NIH expects registration 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:

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.

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights laws that prohibit discrimination on the basis of race, color, national origin, disability, age and, in some circumstances, religion, conscience, and sex. This includes ensuring programs are accessible to persons with limited English proficiency. The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-providers/provider-obligations/index.html and http://www.hhs.gov/ocr/civilrights/understanding/section1557/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 FOA.

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.

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Part 75, 2 CFR Part 200, and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for the HEAL ERN program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the recipients is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the recipients for the project as a whole, although specific tasks and activities may be shared among the recipients and the NIH as defined below. Recipient will retain custody of and have primary rights to the data and software developed under this award, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.

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

  • Determining research approaches, designing protocols with the PD/PIs of the HEAL ERN CCC, DCC, Recruitment Center and biostats core, setting project milestones, and conducting research. The recipient agrees to accept close coordination, cooperation, and participation of NIH staff in those aspects of scientific and technical management of the study as stated in these terms and conditions.
  • Implementation of the protocol, each study, whether a single entity or a consortium of entities, and following the procedures required by the protocol regarding study conduct and monitoring, participant management, data collection, and quality control.
  • Participating in group activities, including the Program Steering Committee, the Clinical Trial Steering Committee, and subcommittees as needed.
  • The Program Steering Committee, which will meet once either in-person or virtually, and additional times if needed by teleconference during the planning year. The Clinical Trial Steering Committees will meet regularly throughout the duration of the study. The Program Steering Committee will recommend the frequency of other in-person and teleconference meetings as needed.
  • Providing reports and data in a timely fashion as agreed upon by the HEAL ERN Program Steering Committee.
  • Submitting all data as soon as they are collected to the HEAL ERN DCC for quality control.
  • Preparing abstracts, presentations, and publications and collaborating Consortium-wide in making the public and professionals aware of the program.
  • Assessing and disseminating data and methods developed for or derived from the HEAL ERN program within and outside the Consortium.
  • Adhering to policies regarding data sharing and publication established by the NIH and the HEAL ERN Program Steering Committee.
  • Abiding by common definitions, protocols, and procedures, as determined in collaboration with the Program Steering Committee.
  • Submitting periodic progress reports in a standard format, as agreed upon by the Program Steering Committee and Clinical Trial Steering Committees.
  • Attending and participating in HEAL ERN Program and Clinical Trial Steering Committee meetings and accepting and implementing decisions by these groups, as appropriate.
  • The PD(s)/PI(s) will manage the involvement of industry or any other third party in the study. Except for licensing of patents or copyrights, support or involvement of any third party will occur only following notification of and concurrence by the NIH.

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

The NIH Project Scientist(s) will have substantial scientific and programmatic involvement during the conduct of this activity through technical assistance, advice, and coordination. The Project Scientist(s) will participate as members of the HEAL ERN Program Steering Committee. The Project Scientist(s) will have the following substantial involvement:

  • Participating through the HEAL ERN Program Steering Committee in addressing issues that arise with HEAL ERN planning, operation, assessment, and data analysis. The Project Scientist(s) will assist and facilitate the group process and not direct it.
  • Serving as a liaison, helping to coordinate activities, including acting as a liaison to other NIH Institutes/Centers, and as an information resource for the recipients. The Project Scientist(s) will also help coordinate the efforts of the HEAL ERN Program with other groups conducting similar efforts.
  • Attending all HEAL ERN Program Steering Committee meetings as a voting member, assisting in developing standard operating procedures, and consistent policies for dealing with situations that require coordinated action. The Project Scientist(s) will be responsible for working with the recipients as needed to manage the logistic aspects of the HEAL ERN program.
  • Reporting periodically on HEAL ERN progress to the NIH Leadership.
  • Serving on subcommittees of the HEAL ERN Program Steering Committee as appropriate.
  • Assisting recipients in the development, if needed, of policies for dealing with situations that require coordinated action.
  • Providing advice in the management and technical performance of the award.
  • Assisting in promoting the availability of the data and related resources developed in the course of this program to the scientific community at large.

In addition, an agency Program Official or IC Program Director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice. The assigned Program Official may also serve as an NIH Working Group Project Scientist(s) to assist the recipient. Prior to funding an application, the Program Official will contact the applicant to discuss the proposed milestones and any changes suggested by NIH staff or the NIH review panel. The Program Official and Project Scientist will negotiate with the applicant and agree on a final set of approved milestones which will be specified in the Notice of Award. The NIH Program Official, in consultation with the Project Scientist and NIH Leadership, will determine if the recipient has met the milestones required for each year of funding.

NIH reserves the right to withhold funding or curtail an award in the event of:

  • Substantive changes in the project, or failure to make sufficient progress toward the work scope with which NIH concurred, or
  • Ethical or conflict of interest issues.

Areas of Joint Responsibility include:

Close interaction among the participating investigators will be required, as well as significant involvement from the NIH, to manage, assess, and implement the HEAL ERN program. The recipients and the Project Scientist(s) will meet through the HEAL ERN Program Steering Committee times during the planning year, and through the Clinical Trials Steering Committees regularly over subsequent years, and on conference calls as needed to share information on methodologies, analytical tools, and preliminary results. PDs/PIs, key co-investigators and pre- and post-doctoral trainees, especially those who are members of under-represented minority groups or those from different but related disciplines, are eligible to attend these meetings.

The HEAL ERN Program Steering Committee will be responsible for coordinating the activities conducted by the program and is the committee through which the individual NIH HEAL ERN Clinical Trials Steering committees will formally interact. The HEAL ERN Program Steering Committee membership will include PD(s)/PI(s) of each HEAL ERN award, other staff as needed, the NIH Project Scientist(s) and the dedicated clinical trial experts from the CCC, DCC, and biostatistics core. The HEAL ERN Program Steering Committee may add additional members, and other government staff may attend the HEAL ERN Program Steering Committee meetings as desired.

The HEAL ERN Program Steering Committee may establish subcommittees as needed to address particular issues, which will include representatives from the program and the NIH and possibly other experts. The HEAL ERN Program Steering Committee will have the overall responsibility of assessing and prioritizing the progress of the various subcommittees.

The HEAL ERN recipient agrees to work collaboratively to:

  • Provide for secure, accurate, and timely data submission.
  • Participate in presenting and publishing new processes and substantive findings.
  • Assess and disseminate HEAL ERN data and resources.
  • Interact with other relevant NIH activities, as needed, to promote synergy and consistency among similar projects.

Dispute Resolution:

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

3. Reporting

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

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement. NIH FOAs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 45 CFR Part 75.301 and 2 CFR Part 200.301.

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

In accordance with the regulatory requirements provided at 45 CFR 75.113 and 2 CFR Part 200.113 and Appendix XII to 45 CFR Part 75 and 2 CFR Part 200, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period.  The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS).  This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313).  As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available.  Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 and 2 CFR Part 200 – Award Term and Condition for Recipient Integrity and Performance Matters.

Section VII. Agency Contacts

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

Application Submission Contacts

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

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

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

Scientific/Research Contact(s)

Wendy Weber, ND, PhD, MPH
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-402-1272
Email: weberwj@mail.nih.gov

Will Aklin
National Institute On Drug Abuse (NIDA)
Phone: 301-827-5909
E-mail: aklinwm@mail.nih.gov

Elena K Gorodetsky
Office Of Research On Women's Health (ORWH)
Phone: (301) 594-9004
E-mail: egorod@mail.nih.gov

Priscah Mujuru, Dr.PH, MPH, RN
National Institute on Minority Health and Health Disparities (NIMHD)
Phone: 301-594-9765
E-mail: mujurup@mail.nih.gov

William P Tonkins
National Heart, Lung, And Blood Institute (NHLBI)
Phone: 301-594-4979
E-mail: william.tonkins@nih.gov

Yolanda F Vallejo
National Center For Advancing Translational Sciences (NCATS)
Phone: (301) 451-1751
E-mail: yolanda.vallejo@nih.gov

Jeri L. Miller, Ph.D.
National Institute of Nursing Research (NINR)
Telephone: 301-594-6152
Email: jmiller@mail.nih.gov

 

Charles H Washabaugh, PhD
National Institute Of Arthritis And Musculoskeletal And Skin Diseases (NIAMS)
Phone: 301-496-9568
E-mail: washabac@mail.nih.gov

Houmam H Araj
National Eye Institute (NEI)
Phone: (301) 435-8166
E-mail: ha50c@nih.gov

Peer Review Contact(s)

Martina Schmidt, Ph.D.
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-594-3456
Email: SchmidMa@mail.nih.gov

Financial/Grants Management Contact(s)

Shelley Headley
National Center for Complementary and Integrative Health (NCCIH)
Phone: 301-594-3788
Email: shelley.headley@nih.gov

Pamela G Fleming
National Institute On Drug Abuse (NIDA)
Phone: 301-480-1159
E-mail: pfleming@mail.nih.gov

Priscilla Grant, JD
National Institute on Minority Health and Health Disparities (NIMHD)
Phone: 301-594-8412
E-mail: pg38h@nih.gov

Nina Hall
National Heart, Lung, And Blood Institute (NHLBI)
Phone: 301-435-0710
E-mail: hallnn@mail.nih.gov

Matthew Thomas Zeback
National Center For Advancing Translational Sciences (NCATS)
Phone: (301) 451-8309
E-mail: matthew.zeback@nih.gov

Kelli Oster
National Institute of Nursing Research (NINR)
Telephone: 301-594-2177
Email: osterk@mail.nih.gov

 

Erik Edgerton
National Institute Of Arthritis And Musculoskeletal And Skin Diseases (NIAMS)
Phone: 301-594-7760
E-mail: erik.edgerton@nih.gov

Karen Robinsonsmith
National Eye Institute (NEI)
Phone: (301) 451-2020
E-mail: kyr@nei.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.

Authority and Regulations

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.

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