Department of Health and Human Services

Part 1. Overview Information

Participating Organization(s)

National Institutes of Health (NIH)

Components of Participating Organizations

National Institute on Drug Abuse (NIDA)

National Institute on Aging (NIA)

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

National Institute of Mental Health (NIMH)

National Center for Complementary and Integrative Health (NCCIH)

National Cancer Institute (NCI)

Funding Opportunity Title
HEAL Initiative: Multilevel Interventions to Reduce Harm and Improve Quality of Life for Patients on Long Term Opioid Therapy (MIRHIQL) (R01 Clinical Trial Required)
Activity Code

R01 Research Project Grant

Announcement Type
New
Related Notices

None

Funding Opportunity Announcement (FOA) Number
RFA-DA-23-041
Companion Funding Opportunity
RFA-DA-23-042 , U24 Resource-Related Research Project (Cooperative Agreements)
Assistance Listing Number(s)
93.279, 93.213, 93.865, 93.866, 93.393, 93.242
Funding Opportunity Purpose

The National Institute on Drug Abuse (NIDA) seeks to support clinical trials that will evaluate multi-level interventions for patients who are using long-term opioid therapy to manage chronic pain for whom risks of continuing opioid therapy may outweigh the benefits of continued opioid use. NIDA seeks studies for pharmacologic management with or without non-pharmacological approaches for managing chronic pain in those currently using long-term opioids. Interventions can target patients, health care providers (inclusive of pharmacists) or health care systems to reduce chronic pain and opioid-related risks and improve quality of life.

This funding opportunity announcement (FOA) 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/.

Key Dates

Posted Date
July 11, 2022
Open Date (Earliest Submission Date)
August 27, 2022
Letter of Intent Due Date(s)

August 27, 2022

Application Due Dates Review and Award Cycles
New Renewal / Resubmission / Revision (as allowed) AIDS Scientific Merit Review Advisory Council Review Earliest Start Date
September 27, 2022 Not Applicable Not Applicable March 2023 May 2023 July 2023

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

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

Expiration Date
September 28, 2022
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

HEAL Initiative

This funding opportunity announcement 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/.

Background

More than 50 million Americans suffer from chronic pain (CP), and approximately 11 million individuals have “high impact chronic pain,” that is, pain that has lasted 3 months or longer and is accompanied by at least one major activity restriction such as being unable to work outside of the home, go to school, or complete household chores. CP treatment and loss of productivity are estimated to cost $635 billion annually in the United States. In recent decades, there has been an over-reliance on the prescription of opioids for chronic pain, contributing to a significant and alarming epidemic of opioid overdose deaths and addiction. Clinical guidelines indicate non-opioid therapy, such as non-opioid pharmacologic agents and nonpharmacologic therapy, is preferred for chronic pain given long-term opioid use elevates risk for opioid misuse, opioid use disorder (OUD), and overdose. Under certain circumstances, opioid tapering is recommended, and patients can exhibit benefits in pain and improved quality in life when tapering of opioid dosages is conducted appropriately and combined with multimodal pain care. Recent NSDUH data suggests that opioid prescribing has sharply declined to levels comparable to those prior to the start of the overdose crisis in the late 1990s.

Despite the efforts to reduce the use of opioids for CP, approximately 13 million Americans with CP continue to be prescribed long-term opioid therapy (LTOT), defined as the use of opioids for 90 days or longer. LTOT may be appropriate for some patients under certain circumstances, mainly when continued opioid use provides benefits that outweigh harms. However, LTOT may have iatrogenic consequences, including a paradoxical increase in pain intensity that can lead to an increase in dose and longer-term use, which increases risk for misuse, OUD, and overdose. Other consequences include physiological problems that range from physical dependence to meeting criteria for OUD. While both physical dependence (e.g., acute tolerance & withdrawal) and OUD (e.g., compulsive use despite harmful consequences) have accepted clinical diagnoses and symptoms, there is a subset of patients on LTOT for whom adverse opioid risks outweigh therapeutic benefit. These patients do not completely meet criteria for OUD and constitute a patient population that is clinically ambiguous and poorly defined. For example, some providers have diagnosed these patients with Complex Persistent Dependence, Complex Persistent Opioid Dependence (CPOD), or protracted abstinence syndrome. Clinical diagnosis notwithstanding, long-term and/or high opioid dose exposure can induce poor pain control, functional decline, psychiatric instability, poor quality of life, and other opioid-related harms. For example, long-term opioid use may result in a failure to fulfill major role obligations at work/school/home, reduced engagement in important social, occupational, or recreational activities, or a rise in engaging in physically hazardous situations. While these behaviors are included in the DSM for defining OUD, if the patient does not meet several criteria related to compulsive drug behaviors, such as unsuccessful efforts to control use, spending a great deal of time obtaining opioids, or craving opioids, providers may be hesitant to make an OUD diagnosis. As a result, this complex population may not receive appropriate OUD treatment services, including access to FDA-approved medications for OUD when appropriate (methadone, buprenorphine, naltrexone), harm reduction services (clean syringes, fentanyl test-strips, naloxone), or behavioral treatment for OUD. These patients are also not likely to receive effective, evidence-based pain management.

Pain specialists or primary care providers may not have sufficient training in managing these opioid-related harms and discontinue pain management treatment of these patients altogether if these behaviors emerge, depriving them of access to evidence-based therapies. Providers may also feel uneasy accepting 'legacy' chronic opioid patients. Under these circumstances, opioids can be abruptly discontinued resulting in withdrawal, a significant increase in pain, and increased suicide risk. In some instances, such patients are not offered multi-disciplinary pain management care, creating 'orphaned' patients who are abandoned by the health care system. In summary, a subset of patients on LTOT do not have access to quality and effective pain treatment, are at elevated risk for transitioning to opioid misuse/OUD, have increased mortality risk, and at the very least, experience poor quality of life.

Following the issuance of federal opioid prescribing guidelines, there have been reports of aggressive and forced tapering, inconsistent with clinical recommendations, which has contributed to this cohort of patients with adverse outcomes. Such patients have increased risk for overdose, mental health symptoms including suicide risk, and damaged patient-provider relationships that adversely impacted patient health. Some clinicians have started transitioning high-risk patients who are unable to successfully taper but do not meet criteria for an OUD diagnosis from full opioid agonist treatment to buprenorphine, a partial opioid agonist. While certain formulations of buprenorphine are FDA approved for pain management, the maximum dosage of these formulations may not be sufficient to transition a patient from high-dose full opioid agonists. However, buprenorphine formulations approved for treating OUD can provide higher doses per day though the safety and efficacy of these higher doses is not well established. As a result, patients are faced with off-label use of MOUD formulations of buprenorphine, which may not be covered by insurance without a formal OUD diagnosis, or which may require clinicians to inappropriately diagnose the patient with OUD that carries stigmatizing and unintended consequences for the patient. Because these patients do not meet DSM criteria for OUD, clinical care for this population can be confusing for providers and equally frustrating for patients. Therefore, additional research is urgently needed to generate evidence for safely managing chronic pain in those maintained on LTOT, those managed with buprenorphine, and those transitioned from LTOT to other pharmacological or non-pharmacological pain management therapies.

In addition to receiving adequate pain care, a subpopulation of individuals on LTOT do not receive access to naloxone, a lifesaving, FDA-approved medication that reverses respiratory depression. In 2018, prescription opioids were involved in approximately 15,000 overdose deaths. Current guidelines support naloxone prescribing for individuals on LTOT who are receiving co-occurring prescriptions for benzodiazepines, are on high dose morphine milligram equivalents, and/or have a history of overdoses. Despite these recommendations, recent estimates suggest that 2.3% of individuals on LTOT receive a naloxone prescription. Further, for those on high dose opioid therapy, only 2.76% of individuals received a concurrent naloxone prescription, and only 0.85% received naloxone among individuals receiving opioids and benzodiazepine prescription. Expanding access to naloxone among this population represents a key component for addressing mortality in patients on LTOT for whom risks outweigh benefits.

Adequate care for patients on LTOT requires effective interactions between patients and clinicians and between providers and health system leadership, in the context of supportive health system policies; a lack of attention to these complex and dynamic interactions has contributed to the current pain crisis and opioid epidemic. The NIH and the broader HEAL portfolio have supported interventions targeting patients, but less attention has been given to providers, including pharmacists, who care for these complex patients and health care systems that govern care at a larger scale. To address the needs of this complex population, this RFA will support multilevel interventions at the patient, provider, and health system levels to improve pain management, minimize opioid-related harms, and improve the quality of life for patients on LTOT for whom risks outweigh benefits.

Research Objectives

Populations of Interest

Studies supported through this RFA must propose a study of individuals who have chronic pain and have been prescribed opioids for at least 90 days. Individuals should also exhibit behaviors suggesting that harms of continued opioid use may outweigh the benefits of continued opioid use. Applicants should define and justify these risk behaviors in the application. Studies should target a broad range of chronic pain conditions within the selected population (i.e., a single chronic pain condition within the proposed sample is discouraged).

Interventions of Interest

Interventions of interest can target patients, providers, or health systems. Providers include any health care provider who may provide treatment for this population, including pharmacists. Applicants are encouraged to examine the existing HEAL and NIH portfolio to avoid scientific overlap. Examples of interventions that are of greatest interest for evaluation include, but are not limited to:

  • Patient-facing (Interventions for patients)
    • Studies aimed at establishing the best evidence and practices for transitioning patients from full opioid agonists to buprenorphine, including assessment of transition processes, safety, ideal starting dose, formulation, and administration frequency; conducted alone or in tandem with evidence-based non-opioid pharmacologic and nonpharmacologic therapies.
    • Studies of flexible, safe, patient-centered opioid tapering schedules and strategies; conducted alone or in tandem with evidence-based non-opioid pharmacologic and nonpharmacologic therapies.
  • Provider/Pharmacist-facing: applicants are encouraged to measure changes in clinical decision making/care and patient outcomes in any proposed educational/training interventions.
    • Training and other educational interventions that inform providers about appropriate tapering strategies and can help remediate inappropriate/rapid opioid tapers.
    • Training and other educational interventions to promote understanding of how to assess the benefits and risks of continued opioid therapy, how to communicate clinical decisions about LTOT with patients through a shared decision-making approach, and continued screening for pain, opioid-related risks (inclusive of patients at elevated risk of suicide and/or worsening mental health), and quality of life.
    • Training and other educational interventions that help providers understand the distinctions among OUD, misuse, tolerance, physical dependence, and difficulty with tapering, and how to integrate multidisciplinary pain treatment and addiction services. Of note, connection to appropriate care includes coordinated care with other health care providers and cannot consist solely of a referral or warm hand off. Ideally, providers with different specialities should collaborate in tandem to manage the treatment plan for these patients.
    • Interventions that increase providers acceptance and retention rate of patients on LTOT in clinical care, while reinforcing evidence-based pain management and interventions that reduce opioid related harms and improve quality of life.
  • Health-system-facing
    • Interventions that increase naloxone distribution and overdose education for the patient and caregivers/family/friends for patients who are at higher risk of respiratory failure (e.g., elderly populations, high dose opioid MMEs, receiving co-prescriptions of benzodiazepines, prior overdose history, etc.)
    • Interventions that increase routinely screening for fentanyl in urine drug screens and use of fentanyl test strips when appropriate.
    • Research that tests or compares research-informed strategies for promoting uptake and sustained implementation of screening of opioid-related risks, inclusive of patients at elevated risk of suicide and/or worsening mental health.
    • Interventions that increase health-system acceptance and retention rate of patients on LTOT in clinical care, while reinforcing evidence-based pain management and interventions that reduce opioid related harms and improve quality of life.
    • Health-system wide training of providers on appropriate tapers, OUD/misuse diagnosis, and assessing the benefits and harms of continued opioid use to make decisions about continuance of LTOT.
    • Interventions that leverage multi-disciplinary or inter-disciplinary pain management and addiction treatments for appropriate patients, including coordinated care models.

Outcomes of Interest

Regardless of the targeted population for the intervention, the application must include measurement of patient-level outcomes. Pain outcomes must be included, and applicants must collect the chronic pain common data elements. In addition, applicants must measure outcomes related to opioid-related harms and quality of life outcomes. For the purposes of the RFA, definitions of these constructs are provided below:

  • Chronic Pain: Pain outcomes must cover the 9 chronic pain domains specified by HEAL, including pain intensity, pain interference, physical functioning/QOL, sleep, pain catastrophizing, depression, anxiety, global satisfaction with treatment, and substance use screening.

  • Opioid-related harms (ORH): ORH outcomes should be related to the progression from opioid dependence to misuse to OUD, and overdose. Additionally, other ORH outcomes may include changes in severity of mental health conditions and suicide ideation. Examples of outcomes include but are not limited to: fatal and nonfatal overdose, use of illicit substances, misuse/overuse of other drugs of abuse (e.g., alcohol, stimulants, cannabis), suicide thoughts and behaviors or exacerbation of mental health disorders (e.g., MDD, GAD, PTSD), and changes in meeting the number of DSM criteria for OUD. Of note, some of the DSM criteria can be viewed as quality of life outcomes (e.g., failure to fulfill major role obligations at work/school/home, reduced engagement in important social, occupational or recreational activities, or a rise in engaging in physically hazardous situations).

  • Quality of Life (QoL): QoL can be measured in a number of ways. Appropriate domains include but are not limited to: (1) disease state and physical symptoms, (2) functional status (e.g., performing daily activities), (3) psychological and emotional functioning, and (4) social functioning. Applicants are encouraged to measure all of these domains.

Across the ORH and QoL constructs, applicants are encouraged to define and justify outcome selection.

Applicants should attend to the scalability, sustainability, and implementation potential of the intervention. To this end, applicants are encouraged to measure outcomes at 6-months post-intervention. Hybrid effectiveness-implementation study designs are also encouraged. Efficacy trials will be accepted. The study design is expected to match with the evaluation research question. Finally, applicants are encouraged to consider study design that is informed by the perspectives of racial and ethnic minority groups, organizations or communities, as well as geographic needs that may be unique to rural areas.

Whenever possible, awardees under this funding announcement will be encouraged to harmonize data collection outcomes on opioid-related harms and quality of life and synergize with the IMPOWR network - see the section below. Data harmonization efforts are expected to occur during the first year of the grant award.

Health Systems of Interest

While treatment of patients on LTOT whose opioid treatment risks may outweigh opioid benefits can occur in a range of health care settings. Settings proposed for this funding opportunity should consistently serve a high volume of patients on LTOT and support ongoing adherence, retention, and follow-up care for this patient population. Selection of the health care setting should include a justification as to why findings from this setting will have a high impact on clinical care from a public health perspective. Applicants are encouraged to include a multi-site/clinic design whenever possible.

Engaging Patients with Lived Experience

The studies funded under this announcement must improve the lives of patients on LTOT for whom opioid related harms outweigh the benefits. To underscore the importance of their perspectives in HEAL-funded research, applications must include a minimum of two patients with lived experience or representatives from patient advocacy groups. The applicant must detail how their expertise will be integrated throughout the research process, including research design, conduct, and dissemination of study findings. Applicants are encouraged to work with patients with lived experience to identify data outcomes of interest to this funding opportunity.

Expected Activities of Coordination

Research studies funded under this announcement will be part of a larger program, which will consist of R01-level grants and a Resource Center. Key responsibilities for this Resource Center include: (1) Provide logistical and coordination support for the broader MIRHIQL program; (2) Create a risk-benefit decision tool to assist providers in determining when opioids should be continued as prescribed, tapered, or tapered and discontinued; (3) Create a clinical definition, identifying associated symptoms/behaviors, and generating a screening tool for individuals on LTOT for whom harms outweigh the benefits; (4) Validate the clinical definition, associated behaviors and symptoms, and screening tool in an independent study. To better understand the research goals of this initiative, applicants should carefully read the companion Resource Center RFA (RFA-DA-23-042). Whenever appropriate, collaboration between Resource Center and awardees from this RFA may occur to advance the scientific knowledge and/or stated goals of either RFA program. For example, these synergistic activities may include common definitions of chronic pain, opioid-related harms, and quality of life measures. Or, awardees from this RFA may serve on the Resouce Center Community Steering Committee.

It is expected that all awardees under this RFA will harmonize CDEs, especially as it pertains to chronic pain characterization, opioid-related harms, and quality of life. It is expected that this data harmonization process will occur during a kick-off meeting and conclude within the first year of the grant award. Awardees from RFA-DA-23-041 are expected to participate on a working group to harmonize CDEs and one PD/PI representative from each award (from RFA-DA-23-041 only) will have voting authority. Whenever appropriate, awardees under RFA-DA-23-041 are expected to also harmonize with IMPOWR (see below). Of note to this RFA, the Resource Center will also assist in coordinating any data harmonization efforts between the R01 awards on measuring opioid-related harms, pain management care, and quality of life, to occur within the first year of the grant award. The Resource Center will also be responsible for programming the CDEs into RedCap to enable data harmonization and assisting the IMPOWR Coordination & Dissemination Center with other infrastructure activities to support data harmonization and network collaborations.

Additionally, research studies funded under this announcement are expected to interact with the HEAL IMPOWR network. This network is intended to create multidisciplinary team science collaborations to develop effective interventions, best models of care for delivery of services, and sustainable implementation strategies for access to quality care for complex patients with chronic pain (CP) and opioid use disorder (OUD) or opioid misuse. Along a continuum of opioid-related harm severity, the population of interest under this current funding announcement precedes populations that misuse opioids or have been diagnosed with OUD. Thus, it would be beneficial to the research field and clinical practice to better understand how this population is similar to and distinct from populations who already have been diagnosed with OUD. Expected activities of coordination with the IMPOWR networks includes but are not limited to: harmonized data collection with IMPOWR when appropriate, participation at annual in-person meetings, data sharing with IMPOWR when appropriate, and participation on IMPOWR workgroups when appropriate. Applicants must share data and metadata with the IMPOWR coordination center. With this goal in mind, applicants must collect data in RedCap and share metadata to enable data harmonization. A complete list of IMPOWR common data elements can be found on the IMPOWR homepage. These expectations will be clearly defined at a kick-off meeting to occur during Fall 2023.

Pre-Application Consultation

Potential applicants are strongly encouraged to consult with NIDA Program staff early in the application development process. This early contact will provide an opportunity to discuss and clarify NIH policies and guidelines, including the scope of the project relative to the HEAL initiative mission and intent of this FOA. Inquiries may be emailed to: MIRHIQL@nih.gov. A technical assistance webinar for applicants to the MIRHIQL initiative will be held on July 25th, 2022 at 12:30 pm EST. Information, including links, will be posted here: https://nida.nih.gov/news-events/meetings-events.

The following applications will be considered non-responsive and will not be reviewed:

  • Applications that do not include a population on long-term opioid treatment (>90 days of use) for whom adverse opioid risks outweigh therapeutic benefit. The selected population should target a broad range of chronic pain conditions.
  • Applications that do not measure chronic pain, reduced opioid-related harms and improved quality of life.
  • Applications that do not evaluate an intervention that targets patients on LTOT for whom opioid risks outweigh harms, providers (inclusive of pharmacists), or health systems.
  • Applications that do not include a minimum of two persons with lived experience in the research team

Special Considerations:

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.

In addition, awardees are expected to participate in an annual meeting that brings together early-career pain researchers funded at NIH and their mentors. This meeting will be executed by the Coordinating Center for National Pain Scientists Career Development (CCNPS). The purpose of these meetings is to enhance mentorship and training, to collaborate with pain researchers across the continuum of pain research, and build relationships to enhance research and potentially collaborate with researchers outside of their institution. For more information on the CCNPS, please review RFA-NS-22-060.

Diversity: In addition to scientific diversity, applicants should strive to incorporate diversity in their team development plan. Research shows that diverse teams working together and capitalizing on innovative ideas and distinct perspectives outperform 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. In spite of tremendous advancements in scientific research, information, educational and research opportunities are not equally available to all. NIH encourages institutions to diversify their student and faculty populations to enhance the participation of individuals from groups that are underrepresented in the biomedical, clinical, behavioral, and social sciences. Please refer to Notice of NIH's Interest in Diversity NOT-OD-20-031 for more details.

Points to Consider Regarding Early Stage Investigators: Pain treatment in this complex population is identified as an under-resourced medical need and has received limited research attention. To assure a sustained workforce and effort toward identifying and developing effective pain treatment for these minority health and NIH-designated populations that experience health disparities, applicants are strongly encouraged to indicate how they will include early-stage investigators in this funding opportunity. Early-stage investigators are not expected to have experience in all areas, but have to demonstrate experience/knowledge that can add to the advancement of the study.

Points to Consider Regarding Tobacco Industry Funding of NIDA Applicants: The National Advisory Council on Drug Abuse (NACDA) encourages NIDA and its grantees to consider the points it has set forth with regard to existing or prospective sponsored research agreements with tobacco companies or their related entities and the impact of acceptance of tobacco industry funding on NIDA's credibility and reputation within the scientific community. Please see https://nida.nih.gov/about-nida/advisory-boards-groups/national-advisory-council-drug-abuse-nacda/points-to-consider-regarding-tobacco-industry-funding-nida-applicants#:~:text=NIDA%20must%20make%20research%20funding,reputation%20within%20the%20scientific%20community () for details.

Data Harmonization for Substance Abuse and Addiction via the PhenX Toolkit: NIDA strongly encourages investigators involved in human-subjects studies to employ a common set of tools and resources that will promote the collection of comparable data across studies and to do so by incorporating the measures from the Core and Specialty collections, which are available in the Substance Abuse and Addiction Collection of the PhenX Toolkit (www.phenxtoolkit.org). Please see NOT-DA-12-008 (http://grants.nih.gov/grants/guide/notice-files/NOT-DA-12-008.html) for further details.

Establishment of a Standard delta-9-THC Unit to be used in Research: Applications proposing research on cannabis or its main psychotropic constituent delta-9-THC are required to measure and report results using a standard delta-9-THC unit in all applicable human subjects’ research. The goal is to increase the comparability across cannabis research studies. A standard delta-9-THC unit is defined as any formulation of cannabis plant material or extract that contains 5 milligrams of delta-9-THC. A justification should be provided for human research that does not propose to use the standard unit. Please see https://grants.nih.gov/grants/guide/notice-files/NOT-DA-21-049.htmlfor additional details.

Points to Consider Regarding Mental Illness Research: Effective prevention and treatment of mental illness have the potential to reduce morbidity and mortality associated with intentional injury (i.e., suicide attempts and deaths, see: www.suicide-research-agenda.org). Lack of attention to the assessment of these outcomes has limited our understanding regarding the degree to which effective mental health interventions might offer prophylaxis. Accordingly, where feasible and appropriate, NIMH encourages effectiveness research that includes assessment of suicidal behavior in clinical trials in response to this FOA using strategies that can facilitate integration and sharing of data (e.g., see NOT-MH-15-009 and https://www.phenxtoolkit.org/ for example constructs and corresponding assessment strategies)..

Further, in an effort to better understand the intervention effects on clinical outcomes of interest, design aspects should be consistent with the NIMH experimental therapeutics approach (see Support for Clinical Trials at NIMH). Under this approach, studies should be designed to examine whether the intervention engages the proximal target(s)/mechanism(s) presumed to underlie the effect of the intervention (i.e., the mechanism presumed to account for changes in the clinical outcomes of interest).

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

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

Section II. Award Information

Funding Instrument

Grant: A support mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity.

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).

Funds Available and Anticipated Number of Awards

The HEAL Initiative intends to commit $6.75 million total costs in FY 2023 to fund 6-7 awards.

Award Budget

Application budgets are limited to $750,000 in direct costs per year but must reflect the actual needs of the project.

Award Project Period

The maximum project period is 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 Government

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

Other

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

  • System for Award Management (SAM)– Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
    • NATO Commercial and Government Entity (NCAGE) Code – Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
    • Unique Entity Identifier (UEI)- A UEI is issued as part of the SAM.gov registration process. The same UEI must be used for all registrations, as well as on the grant application.
  • eRA Commons - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their full SAM and Grants.gov registrations; all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
  • Grants.gov – Applicants must have an active SAM registration in order to complete the Grants.gov registration.

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

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

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 diverse backgrounds, including underrepresented racial and ethnic groups, individuals with disabilities, and women are always encouraged to apply for NIH support. See, Reminder: Notice of NIH's Encouragement of Applications Supporting Individuals from Underrepresented Ethnic and Racial Groups as well as Individuals with Disabilities, NOT-OD-22-019.

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

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:FOAReviewContact@csr.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.

Facilities & Other Resources: Applicants should provide an explanation of resources available from each project/performance site on the "Facilities and Other Resources" attachment.

Specifically:

  • Data should be presented on the number of patients on long-term opioid therapy (i.e., > 90 days) eligible for recruitment to meet the goals of this RFA. This may be presented broadly for the pool of sites and/or specifically for each proposed site, depending on the study design.
  • The capacity to recruit additional sites, if needed, should be described.
  • As noted in the Research Strategy Instructions, letters of support are required for each proposed research site. If a study design proposes recruiting sites as part of a study design, strong justifications demonstrating the feasibility of recruitment and a strong justification for the selection of this strategy must be included.
SF424(R&R) Senior/Key Person Profile

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

With the following additional instructions:

PD/PIs are required to expend at least 2.0 person-months effort annually on the award over the entire period of support. In a multi-PI application, at least one PD/PI is required to commit a minimum of 2.0 person-months annually over the life of the grant award.

Senior/Key Personnel biosketches should describe recent experience and participation in randomized clinical trials, preferably of a multisite nature. Applicants are expected to provide evidence of their unique strengths, accomplishments and capabilities to contribute to shared activities across multiple funded projects, with an eye towards data harmonization efforts. Applicants should provide their ability to engage patients with lived experience. Applicants should provide evidence of expertise in the conduct of clinical trials, particularly collaborative, pragmatic, randomized clinical trials. Applicants should detail their experience working with patients on LTOT for whom risks outweigh benefits and understand the nuances and complexities of this particular population. Persons responsible for participant recruitment should be well-qualified with extensive experience in participant enrollment, data collection, and data management.

PD/PIs and other key personnel with substantial time commitments to the network should expect to actively participate in a wide variety of activities, including, but not limited to: actively engaging in data harmonization efforts, making data from their study available to others, and engaging with the IMPOWR network.

R&R or Modular Budget

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

With the following additional instructions:

Applications must include a minimum of 2 patients with lived experience and/or representatives from patient advocacy organizations. Budgetary support might include allowable salary support or honorarium, travel, and per diem costs. If applications have not predetermined patients with lived experience, it is appropriate to set aside a number of slots to fill in after the stakeholder needs have been established based on the research projects.

Requirements for Participating in Additional Research Activities:

Budgets should include funds for travel for the PD(s)/PI(s), 1 patient with lived experience/patient organization representative, and up to three additional project staff to participate in in-person meetings once per year, every year of the award. Whenever possible, these meetings will occur together with the annual in-person IMPOWR executive committee meetings. An additional in-person kickoff meeting should be included in year one budget of the award to discuss data harmonization policies and procedures. In the event in-person gatherings are not possible due to the COVID-19 pandemic, applicants should plan to conduct these meetings virtually.

In addition to the annual in-person meetings, representatives from each award are expected to participate in virtual meetings that will occur quarterly. PI(s) and 1 patient with lived experience/patient organization representative should be present from each award at these virtual meetings.

In addition to executing the proposed protocol, applicants will be expected to participate in efforts to harmonize data collection and participate in other trans-HEAL activities and workgroups created to support synergistic activities across the network and across HEAL. Applicants will also be required to provide the IMPOWR Coordination and Dissemination Center with quarterly, accurate data on human subject recruitment/enrollment/and progress to facilitate the ability of this center to provide NIH with accurate data-driven updates of network progress. Applicants are expected to share data and metadata with the IMPOWR Coordination & Dissemination Center on a regular basis. Time should be budgeted to participate in such activities.

Finally, awardees are expected to participate in an annual meeting that brings together early-career pain researchers funded at NIH and their mentors. This meeting will be executed by the Coordinating Center for National Pain Scientists Career Development (CCNPS). The purpose of these meetings are to enhance mentorship and training, to collaborate with pain researchers across the continuum of pain research, and build relationships to enhance research and potentially collaborate with researchers outside of their institution. For more information on the CCNPS, please review RFA-NS-22-060.

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:

Applicants must address:

  • individuals who have chronic pain who have also received prescription opioids for at least 90 days.  Individuals should also exhibit behaviors suggesting that harms of continued opioid use may outweigh the benefits of continued opioid use. Applicants should define and justify these risk behaviors in the application. Studies should target a broad range of chronic pain conditions within the selected population (i.e., a single chronic pain condition within the proposed sample is discouraged).
  • Multi-level interventions that target patients, health care providers (inclusive of pharmacists), or health systems. Applicants are encouraged to measure changes in clinical decision making/care and patient outcomes in any proposed educational/training interventions that target health care providers.
  • Outcomes of interest: applicants must collect chronic pain common data elements, opioid-related risks and quality of life outcomes. Across opioid-related risks and quality of life outcomes, applicants are encouraged to define and justify outcome selection.
  • Engagement with a minimum of two patients with lived experience and/or representatives from patient advocacy groups throughout the research process, including research design, conduct, and dissemination of study findings. Applicants are encouraged to work with patients with lived experience to identify data outcomes of interest to this funding opportunity.
  • Coordination with the other funded awards under this program announcement and the associated Resource Center. Expected activities of coordination includes data harmonization efforts on measuring opioid-related harms, pain management care, and quality of life, to occur within the first year of the grant award. The associated Resource Center will be responsible for programming these outcomes into RedCap and will interface with the HEAL CDE Program Director.
  • Coordination with the IMPOWR network. Expected activities of coordination with the IMPOWR networks includes but are not limited to: harmonized data collection with IMPOWR when appropriate, participation at annual in-person meetings, data sharing with IMPOWR when appropriate, and participation on IMPOWR workgroups when appropriate. Applicants must share data and metadata with the IMPOWR coordination center. With this goal in mind, applicants must collect data in RedCap to enable data harmonization.
  • There needs to be an enrollment milestone plan and timeline.

Applicants are encouraged to attend to:

  • Health system of interest and why this is a high impact setting from a public health perspective.
  • Scalability, sustainability, and implementation potential of the intervention. To this end, applicants are encouraged to measure outcomes at 6-months post-intervention and use hybrid effectiveness-implementation study designs. Efficacy trials will be accepted. The study design is expected to match with the evaluation research question. Finally, applicants are encouraged to consider study design that is informed by the perspectives of racial and ethnic minority groups, organizations or communities, as well as geographic needs that may be unique to rural areas.

Letters of support:

Letters from all clinical research sites proposed across the research projects are required.

A minimum of two letters of support from patients with lived experience and/or are representatives from patient organizations are encouraged, but not required. Describe how these individuals will contribute to the research design, subject recruitment, treatment retention, and engagement in follow-up care.

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.

HEAL Data Sharing Plan

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. Data generated by HEAL Initiative-funded projects must 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. Guidelines for complying with the HEAL Public Access and Data Sharing Policy can be found at https://heal.nih.gov/data/complying-heal-data-sharing-policy. Resources and tools to assist with data related activities can be found at https://www.healdatafair.org/.

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.
  • To the extent possible, HEAL awardees are expected to integrate broad data sharing consent language into their informed consent forms and align study consent language with data access and re-use requirements as defined by repository HEAL investigators select to store their HEAL data long-term.

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

  • Elements of an NIH Data Management and Sharing Plan (NOT-OD-21-014)
  • NIH has provided guidance around selecting a repository for data generated by NIH-supported research and has developed desirable characteristics for all data repositories (NOT-OD-21-016).
  • NIH encourages the use of data standards including the PhenX Toolkit (www.phenxtoolkit.org) (for example, see NOT-DA-12-008, NOT-MH-15-009)
  • Data should be organized according to a standard model that is widely accepted within the field. An example for the clinical research studies would be the OMOP Common Data Model, which has also been successfully adapted for use with observational (including survey) studies more generally. In addition, the HL7 FHIR® (Fast Healthcare Interoperability Resources) standard (NOT-OD-19-122) may facilitate the flow of data with EHR-based datasets, tools, and applications.
  • NIH encourages clinical research programs and researchers to adopt and use the standardized set of data classes, data elements, and associated vocabulary standards specified in the United States Core Data for Interoperability (USCDI) standards, as they are applicable (NOT-OD-20-146). Use of the USCDI can complement the FHIR® standard and enable researchers to leverage structured EHR data for research and enable discovery. In addition to USCDI, OMOP, and FHIR standards for enhanced interoperability, investigators and data centers should align their data collection and management practices with recommended guidance emerging from the HEAL CDE and Data Ecosystem programs.
  • Awardees conducting research that includes collection of genomic data should incorporate requirements under the NIH Genomic Data Sharing Policy (NOT-OD-14-124, NOT-OD-15-086).
Appendix:
Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.
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.

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 fieldof the Senior/Key Person Profile form. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

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

See more tips for avoiding common errors.

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

 

Post Submission Materials

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

Section V. Application Review Information

1. Criteria

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

For this particular announcement, note the following:

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

Overall Impact

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

Scored Review Criteria

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

Significance

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

Specific to this FOA: Does the application address scalable, generalizable, and sustainable treatment models in health care settings? Does the application address an intervention at the patient, provider/pharmacist, or health-system level? Does the application include plans to effectively disseminate information to relevant audience and engage patients with lived experience in a meaningful manner? Does the intervention address the needs of patients on LTOT for whom opioid risks outweigh the benefits? Will the proposed study transform our ability to identify patients on LTOT for whom risks outweighs benefits from continued opioid use?

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

Investigator(s)

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

Specific to this FOA: Is the time commitment of the PD/PI (s) and key personnel appropriate and adequate for the stated study goals? Are there clear descriptions of the roles for each of the key personnel involved in the project? Is there expertise representative of pain management, opioid related harms, and quality of life? Is there a PI with knowledge on opioid-related harms ranging from physical dependence to misuse to OUD? Are patients with lived experience/patient organization representatives appropriately represented on the application and is the extent of engagement proposed adequate for the proposed work? Does the team have statistical expertise to support the goals of the RFA?

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

Innovation

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

Specific to this FOA: Does the application challenge and seek to shift current research or clinical paradigms thatmeet the unique needs of individuals on LTOT? Are there innovative approaches to engaging with patients with lived experience/patient organization representatives in a meaningful manner?

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

Approach

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

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?

Specific to this FOA: Is a strong justification provided for selecting the health care settings? Are the sites selected well suited for the goals of the RFA? Are there strong justifications for the proposed interventions? Does the study power account for the RFA-specified primary outcomes on chronic pain (and specifically, the HEAL Pain CDEs), opioid-related harms, and quality of life outcomes? Is there a clear commitment to participate in synergistic activities with the Resource Center and other funded R01s under this announcement? Is there a clear commitment to participate in synergistic activities with the IMPOWR network? In addition to informing the research design, are there plans to utilize these patient perspectives to inform subject recruitment, treatment retention, and engagement in follow-up care? Does this design test interventions or strategies that are potentially generalizable to other communities or settings? Are plans for data collection, harmonization, management, quality control, and sharing appropriate and adequate for the proposed work? Are a detailed study design and statistical analysis plan (including power analysis) included in the application? Has the applicant included a feasible and appropriate enrollment plan? For educational/training interventions that target health care providers, do applicants measure changes in clinical decision making/care and patient outcomes? Does the application include an approprate Data Sharing Plan?

Does the application adequately address the following, if applicable

Study Design

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

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

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

Data Management and Statistical Analysis

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

Environment

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

Specific to this FOA: Do the research performance sites named in the application have the infrastructure (staff and participant sample size) necessary to deliver evidence-based treatment interventions?

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.

Study Timeline


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

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

Protections for Human Subjects

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

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

Inclusion of Women, Minorities, and Individuals Across the Lifespan

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

Vertebrate Animals

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

Biohazards

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

Resubmissions

Not applicable.

Renewals

Not applicable.

Revisions

Not applicable.

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.

Applications from Foreign Organizations

Not Applicable.

Select Agent Research

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

Resource Sharing Plans

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: (1) (2) Sharing Model Organisms; and (3)  Genomic Data Sharing Plan (GDS).

Authentication of Key Biological and/or Chemical Resources:

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

Budget and Period of Support

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

2. Review and Selection Process

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

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

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

Appeals of initial peer review will not be accepted for applications submitted in response to this 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 appropriate national Advisory Council or Board. The following will be considered in making funding decisions:
  • Scientific and technical merit of the proposed project as determined by scientific peer review.
  • Availability of funds.
  • Relevance of the proposed project to program priorities.

3. Anticipated Announcement and Award Dates

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

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

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

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

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

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

Should the applicant organization successfully compete for an award, 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 (including gender identity, sexual orientation, and pregnancy). This includes ensuring programs are accessible to persons with limited English proficiency and persons with disabilities. The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-providers/provider-obligations/index.html and https://www.hhs.gov/civil-rights/for-individuals/nondiscrimination/index.html

HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research. For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this 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

Not Applicable

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

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

Section VII. Agency Contacts

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: 301-637-3015

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)

Shelley Su, Ph.D.
National Institute on Drug Abuse
Telephone: 301-402-3869
Email: MIRHIQL@mail.nih.gov

Pete Murray, Ph.D.
National Center for Complementary and Integrative Health (NCCIH)
Phone: 301-496-4054
Email: peter.murray@nih.gov

Devon Oskvig, Ph.D.
National Institute on Aging (NIA)
Phone: 301-827-5899
Email: devon.oskvig@nih.gov

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

Stephen O'Connor, Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 301-480-8366
Email: stephen.o'connor2@nih.gov

Alexis Bakos, PhD, MPH, RN
National Cancer Institute (NCI)
Phone: 301-921-5970
Email: alexis.bakos@nih.gov
 

Peer Review Contact(s)

Center for Scientific Review (CSR)

Email: FOAReviewContact@csr.nih.gov

Financial/Grants Management Contact(s)

Pam Fleming
National Institute on Drug Abuse (NIDA)
Telephone: 301-480-1159
Email:pfleming@mail.nih.gov

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

Jeni Smits
National Institute on Aging (NIA)
Phone: 301-827-4020
Email: jeni.smits@nih.gov

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

Tamara Kees
National Institute of Mental Health (NIMH)
Telephone: 301-443-8811
Email: tkees@mail.nih.gov

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

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