Part 1. Overview Information

Key Dates

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.

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

Purpose

The National Institutes of Health (NIH) intends to establish an Integrative Management of chronic Pain and OUD for Whole Recovery (IMPOWR) network consisting of clinical research centers, which will be supported by a single Coordination and Dissemination center. 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. The network will be part of the NIH’s Helping to End Addiction Long-term (HEAL)^SM Initiative to speed the development and implementation of scientific solutions to the national opioid public health crisis. The NIH HEAL Initiative will bolster research across NIH to (1) improve treatment and prevention of opioid misuse and opioid use disorder and (2) enhance pain management.. Applicants interested in pursuing research examining comorbid OUD and other health conditions with or without suicide risk are encouraged to respond to NOT-MH-21-005.

This FOA seeks research center applications to develop approaches, models, delivery, and implementation of care for co-occurring chronic non-cancer pain and OUD/misuse, which will be supported by a single Coordination and Dissemination Center (RFA-DA-21-029).

Background

The ongoing opioid epidemic and the chronic pain (CP) crisis represent significant public health problems with unmet needs. The opioid epidemic was fueled by three waves of opioid use: (1) the overprescribing of prescription opioids to manage pain; (2) the increased use of illicit opioids, such as heroin; and (3) the increased number of overdose deaths involving powerful synthetic opioids, like fentanyl. As a result, an estimated 2 million individuals have an opioid use disorder (OUD), and to date, approximately 450,000 people have died from an overdose involving prescription or illicit opioids. In addition, nearly 10 million Americans misuse opioids, using them differently than prescribed or for the euphoric effects of the drug, which may elevate the risk for developing OUD. More than 50 million Americans suffer from chronic pain, and approximately 20 million individuals have severe CP that interferes with life or work activities. CP treatment and loss of productivity are estimated to cost $635 billion annually in the United States. Both opioid over-prescribing and restrictions on opioid prescribing have led to unintended consequences for many who have CP. People with pain may rely on opioids for pain relief in the absence of other effective treatments, and some turn to misuse or to illicit drug use for pain relief as health care professionals reduce or eliminate access to opioids for pain management. In addition, a subset of individuals with OUD may go on to develop acute or chronic pain. As a consequence, too many people suffer from both CP and OUD. These complex patients often do not respond well to current treatments for pain or OUD, face challenges of stigma, and often have limited or no access to quality care. Evidence-based integrated treatments and models of care that are effective and accessible for patients with co-occurring conditions are urgently needed.

Care for patients who have co-occurring CP and OUD may be further complicated by additional comorbid mental health or substance use disorders. A significant number of individuals self-medicate for pain with alcohol and/or have Alcohol Use Disorder. Furthermore, the prevalence of General Anxiety Disorder and Major Depressive Disorder is high among individuals with co-occurring OUD and CP. Patients who have co-occurring mental health or substance use diagnoses often have worse pain outcomes and may complicate effective management of comorbid CP and OUD. For this reason, the development of integrated treatments, integrated care delivery models, and implementation strategies should not ignore these comorbidities and opportunities may exist to attend to these psychiatric comorbidities in order to treat the whole patient.

Health care services for patients with both CP and OUD are fragmented in the United States. Providers in pain clinics and primary care clinics have evidence-based pain management treatments for patients with CP, such as opioid or non-opioid medications, interventional treatments, and non-pharmacological pain management strategies. They also have tools to assess and monitor patient responses to opioid analgesics, compliance with treatment agreements to assure safe and effective opioid prescription use, and monitor behaviors indicative of misuse while managing their pain. However, if a patient exhibits opioid misuse, the patient may be discharged from a pain clinic or a primary care clinic and referred to substance use or OUD treatment programs. While skilled at treating OUD, these programs often lack the expertise and resources to manage co-occurring CP. Healthcare providers lack tools and treatment guidelines and therefore, experience great difficulty treating patients with co-occurring CP and OUD. There is limited research on how to effectively and concurrently treat a patient’s CP and OUD. For example, there is a lack of evidence regarding which medications and/or dosages can be used safely and effectively to treat these patients. There also is a lack of evidence about how best to integrate and dose pharmacotherapies with non-pharmacological behavioral approaches and complementary interventions to treat patients with CP and OUD. The overall goal of these companion FOAs is to develop, evaluate, disseminate, and implement patient-centered and integrated treatments and models of care that are safe, effective, and accessible to complex patients with both CP and OUD.

While challenging, strategies can be pursued to safely and effectively respond to the needs of this complex patient population. Opportunities exist to leverage the effective treatment modalities targeting CP or OUD alone by integrating them to address the needs of individuals with both conditions. Medications for OUD (MOUDs; e.g. buprenorphine, methadone, and naltrexone) can effectively treat OUD and are often used in combination with behavioral approaches to improve treatment adherence and recovery outcomes. Pharmacological treatments and complementary medicine approaches such as mindfulness, cognitive behavioral therapy, acupuncture, exercise, and physical therapy can be effective for treating CP. Additionally, medical devices such as transcranial magnetic stimulation (TMS) are showing promise for managing CP and drug craving in individuals with OUD. Despite scientific evidence for effectiveness of such approaches for OUD or pain, we have little knowledge of how best to leverage, integrate, and deliver these treatments for co-occurring CP and OUD/misuse. Access to quality care for many, especially underserved populations, who have CP or OUD presents even greater challenges for care delivery to people with both conditions. Effort is needed to address the barriers that lead to fragmented health care delivery for CP and OUD. Best models for integrated care and best approaches to implementation need to be explored and evaluated to maximize sustained access to quality care. Bringing together scientists, patients, and practitioners with the appropriate expertise to develop data-driven best practices to manage CP and OUD is an important part of the formula needed to improve the health of this population.

This FOA seeks research center applications to develop approaches, models, delivery, and implementation of care for co-occurring chronic non-cancer pain and OUD/misuse. Awards made under the current FOA will be supported by an associated Coordination and Dissemination Center (see RFA-DA-21-029). Applicants interested in pursuing research examining comorbid OUD and other health conditions with or without suicide risk are encouraged to respond to NOT-MH-21-005.This FOA encourages innovative multidisciplinary approaches across specialties to identify appropriate treatment interventions and outcome measures relevant for individuals with CP and OUD and associated comorbidities.

HEAL Initiative

This FOA is part of the NIH’s Helping to End Addiction Long-term (HEAL) initiative to speed the development and implementation of scientific solutions to the national opioid public health crisis. The NIH HEAL Initiative will bolster research across NIH to (1) improve treatment for opioid misuse and addiction and (2) enhance pain management. More information and periodic updates about the HEAL Initiative are available at: https://www.nih.gov/research-training/medical-research-initiatives/heal-initiative.

Network Structure and Objectives

The network will support multidisciplinary research centers to develop and evaluate integrated interventions, models of care, and implementation strategies that will provide an evidence base for safe, effective, patient-centered treatments and facilitate access to quality care for individuals who have co-occurring CP and OUD. To accomplish this objective, NIH intends to establish a network of investigators at multiple sites and with broad expertise in the areas of CP and OUD/misuse treatment and service delivery which are linked together through a central Coordination and Dissemination center that serves to promote collaboration and communication and to provide shared research resources across the network.

1. Multidisciplinary Research Centers: These programs will be comprised of RM1 centers conducting clinical research and adaptive clinical trials, which would include pragmatic clinical effectiveness, implementation and/or hybrid implementation-effectiveness studies. In support of these clinical research efforts, research centers must maintain continuous engagement with persons with lived experience (PWLE) or representatives from patient organizations and key stakeholders relevant to the research projects. Relevant stakeholders, in addition to PWLE, may include, but are not limited to payors, caretakers, health care providers from multiple disciplines, policymakers, advocacy groups, or professional organizations that create clinical care guidelines. It is expected that awardees will interact extensively with the Coordination and Dissemination center to facilitate and accelerate sharing and dissemination of research resources, protocols, and findings across the network and to appropriate target audiences.
2. Coordination and Dissemination Center: A single Coordination and Dissemination Center will manage logistics, develop and maintain common data elements, disseminate findings and products generated from the research network to broader audiences, coordinate efforts across and between the network, support educational activities, develop novel tools, and identify areas of synergy and opportunities both within and external to the broader NIH HEAL Initiative, including Optimizing Multi-Component Service Delivery Interventions for People with Opioid Use Disorder, Co-Occurring Conditions, and/or Suicide Risk (NOT-MH-21-005), Pragmatic and Implementation Studies for the Management of Pain to Reduce Opioid Prescribing (PRISM), Pain Management Effectiveness Research Network (ERN), Back Pain Consortium Research Program (BACPAC), and/or Behavioral Research to Improve Medication-Based Treatment (BRIM).

Applicants also are encouraged to review a related FOA that will optimize multi-component service delivery interventions for people with OUD and co-occurring conditions (NOT-MH-21-005). Interaction is expected between the IMPOWR network and those from NOT-MH-21-005 and applicants should anticipate the potential for overlapping populations of interests across the studies. The purpose of the related initiative is to support studies that will test (1) overall effectiveness of multi-component interventions for OUD and co-occurring conditions and (2) examine the relative contribution of constituent components to overall effectiveness. This research will streamline service packages so they only include components that drive clinical improvements for complex conditions. Studies are to be highly pragmatic and practice relevant, with designs that balance rigor with time-to-practice urgency. Projects will seek to a) identify constituent components that drive improvements in access, continuity, quality, value, and outcomes of care, for service delivery interventions with previously demonstrated effectiveness as a bundled package; and b) simultaneously test overall effectiveness of the package and its subcomponents, for widely implemented service delivery packages without previously demonstrated effectiveness. Please review NOT-MH-21-005 for detailed information.

A summary of the synergistic and distinct elements between these inter-related FOAs is provided below:

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IMPOWR research centers, the IMPOWR Coordination and Dissemination center and NOT-MH-21-005 awardees are expected to participate in shared executive committee meetings, which will meet quarterly and an annual in-person 2-day meeting throughout the life of the award. These meetings provide a forum to discuss (1) research updates; (2) opportunities of synergy and collaboration (e.g., data harmonization, protocol modifications); (3) develop a bidirectional pipeline between the research projects to facilitate practice-based research and improve early identification, intervention effectiveness, service delivery, and optimal components that are driving integrated care delivery for CP and OUD. It is also expected that IMPOWR research centers, the IMPOWR Coordination and Dissemination center, and NOT-MH-21-005 awardees will participate in workgroups that arise to support synergistic activities across these networks (e.g., publication policy, data policy, stakeholder and patient engagement, biostatistics, and subject recruitment). Finally, IMPOWR research centers, the IMPOWR Coordination and Dissemination center and NOT-MH-21-005 awardees are expected to participate in break-out sessions with other HEAL programs of relevance to this initiative (e.g., PRISM, ERN, BACPAC, BRIM, etc) at the annual HEAL Investigator meeting.

IMPOWR Research Centers: Scope of Activities and Purpose

Populations of Interest

Studies supported through this FOA must recruit individuals who have chronic, non-cancer pain and also exhibit opioid misuse or meet DSM-5 criteria for OUD, including those who are in recovery. For the purposes of this FOA, definitions for CP, OUD, opioid misuse and any attendant psychiatric disorders are provided below:

• Opioid misuse Definition: taking a medication in a manner or dose other than prescribed; taking someone else’s prescription, even if for a legitimate medical complaint such as pain; or taking a medication to feel euphoria (i.e., to get high).
• OUD Definition: The DSM-5 identifies OUD as a problematic pattern of opioid use leading to clinically significant impairment or distress. OUD severity can range from mild (2-3 symptoms), to moderate (4-5 symptoms) and severe (6 or more symptoms). Individuals who are in OUD recovery can also be included in these studies. Of importance, tolerance and withdrawal symptoms represent iatrogenic consequences of chronic opioid consumption and do not meet DSM criteria for mild OUD. Individuals with physical dependence who do not meet any DSM-5 criteria for OUD are NOT a priority for this initiative.
• CP Definition: CP is the presence of pain for at least 3 months. CP is a biopsychosocial condition, resulting from complex genetic-environment interactions and is influenced by dynamic changes in physiological, psychological, and social factors. This RFA will only address non-cancer chronic pain. Pain associated with ongoing cancer or cancer treatment and acute pain are NOT a priority for this RFA.
• Co-occurring psychiatric Conditions: Individuals with frequently co-occurring conditions may complicate effective treatment of CP and OUD/misuse. This FOA prioritizes the following psychiatric disorders: Alcohol Use Disorder (AUD) or heavy alcohol consumption (defined as more than 4 drinks on any day and more than 14 per week for men; and more than 3 drinks on any day and more than 7 per week for women), Generalized Anxiety Disorder (GAD), and Major Depressive Disorder (MDD). Importantly, patients with these common comorbidities should be not be excluded from these studies. Given the prevalence of their co-occurrence with CP and OUD/misuse and potential to affect pain, applicants are encouraged to develop interventions that also address AUD, GAD, and MDD to target CP and OUD. This RFA will also encourage consideration of the influence of AUD, GAD, and MDD on the efficacy of CP and OUD/misuse interventions when present.

High Priority Research Clusters

It is expected that applications will contain a multidisciplinary team to address the challenges associated with effective, safe and integrated health care delivery for individuals with co-occurring CP and OUD that spans the continuum of opioid misuse, OUD treatment, and recovery. The research centers will conduct clinical research and adaptive trials which could include pragmatic effectiveness, implementation, and hybrid implementation-effectiveness studies. Each application must propose two to three research projects that address the high priority research clusters listed below. These include effectiveness trials of evidence-based interventions for both OUD/misuse and CP; evaluation of models of integrated care delivery; and identifying and testing strategies for implementing integrated effective therapies. Of note, for the Integrated Care Models research cluster, study designs must ensure coordinated and sustained linkage between CP and OUD/misuse specialists to provide meaningful and integrated care delivery for the patient. Study designs that propose referrals to a pain or OUD/misuse health care provider as a model of care are not appropriate for this FOA.

Applicants are NOT required to address all three research clusters. Applicants have the flexibility to select any combination of the high priority research clusters and may opt to execute all of the research projects within a single high priority research cluster. More important than any particular combination of clusters is the justification of the approach used based on supporting evidence and the potential for rapid and meaningful impact on patients and health care system practices.

Applicants are encouraged to utilize clinically meaningful resources to enhance sustainability of care and improve patient outcomes (e.g. leveraging electronic health records to integrate care, adoption of mobile technology/telehealth platforms, decision support tools, economic measures, and peer navigation as appropriate to the research).

This initiative will accept applications that propose studies in the following research clusters. Examples of interventions and approaches of interest within each research cluster include but are not limited to:

1. Effectiveness trials on integration of evidence-based interventions for CP and OUD/misuse to provide optimal approaches for treatment of both conditions. This FOA invites a wide range of treatment approaches ranging from pharmacological, behavioral, and/or medical devices (e.g., TMS) that has demonstrated efficacy for treating CP or OUD/misuse. The PI must provide supporting evidence to justify the selection of the intervention for treating both CP and OUD/misuse.

• Determining dosing and scheduling of pharmacological and non-pharmacological interventions to manage comorbid CP pain and OUD/misuse. Of particular interest is how best to manage use of buprenorphine for OUD and CP.
• Determine effectiveness of sequencing and dosing of combinations of multimodal treatments such as MOUDs with non-pharmacological approaches for treating CP (e.g. cognitive behavioral therapy, mind body therapies, physical therapy, acupuncture) or medical devices
• Combining patient-informed opioid tapering approaches with non-pharmacological treatments and/or MOUDs
• Adapting evaluation of EBPs for CP and OUD/misuse to account for comorbidities such as AUD, GAD, MDD, (e.g., considering variables such as treatment sequencing, overlap in prescription medications, patient priorities)

2. Evaluation of Integrated Models of Care Delivery for evidence-based treatments for CP and OUD/misuse

• Collaborative Care models
• Multidisciplinary Stepped Care Approaches
• Hub & Spoke models
• Case Management Approaches

3. Implementation strategies to maximize reach and sustainability of integrated evidence-based practices for pain and OUD/misuse

• Introduce effective integrative approaches into specialty pain programs and OUD treatment settings. For example, test strategies to increase patient access to CP care providers in primary care settings who are certified to prescribe buprenorphine for OUD treatment
• Implement supervised learning/academic detailing on integrated care
• Develop strategies to restructure workflow to facilitate service integration
• Increase uptake and sustained usage of integrated, holistic EBPs to treat the whole patient (i.e., synergistically targeting OUD, CP, and associated comorbidities)

These research clusters were selected based on their potential to provide an evidence base for integrated care for CP and OUD that spans the continuum of opioid misuse and OUD, and to improve access to delivery of quality care that is sustainable and available across affected populations. Applicants are encouraged to include companion research approaches, such as modeling or other creative designs, that could generate results in advance of the clinical trial and complement the clinical trial findings.

In parallel, NIH recognizes the importance of developing novel interventions for treating comorbid CP and OUD, and applicants have the option to propose these types of projects as pilot projects only. Pilot projects do not count towards the two-three research projects requirement.

Definition of a Clinical Research Site

The treatment of comorbid CP and OUD can occur in a diverse range of health care settings; however, a setting selected for this funding opportunity should consistently serve a high volume of patients with comorbid CP and OUD 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 this setting is expected to be a high impact setting from a public health perspective.

Each research cluster has different requirements regarding a multi-site study design. Projects that examine integrated care models between CP and OUD services and projects that test different implementation strategies to maximize existing EBPs in different health care settings must propose a multisite research design. Projects that integrate evidenced-based interventions for treating CP or OUD to effectively treat both conditions do NOT have to meet a multisite requirement, but applicants are encouraged to do so if it is feasible. For multi-site projects, applicants are encouraged to be thoughtful about low-resource communities and/or rural areas that face unique challenges in addressing comorbid CP and OUD.

Applications that propose two research projects within one research cluster are encouraged to identify study designs that are synergistic. For example, the applicant may choose to use the same control sites across the two research projects. In addition to the detailed study design, applicants must provide an analysis plan and power calculation for the multisite study. Sufficient detail must be provided on study design, analysis plan, and power calculations to replicate power calculations and evaluate the assumptions and parameter estimates used in the calculations.

Common Data Elements (CDEs)

Research designs should include a follow-up period of 6 months and ideally, up to a year. Applicants are encouraged to use psychometrically validated instruments, such as those found in PROMIS. Applicants should note that a single composite holistic outcome measure for CP and OUD will be developed by the IMPOWR Coordination and Dissemination Center in collaboration with the awarded research centers and through PWLE engagement. Research centers must use this tool whenever it becomes available to the network. It is expected that all funded programs within this initiative will harmonize common data elements and data collection strategies in Fall 2021, prior to the launch of individual study protocols. Research centers are expected to harmonize common data elements with awardees from NOT-MH-21-005.

OUD/opioid misuse CDEs: Subjects recruited for these studies must have non-cancer CP and meet the definition of opioid misuse or DSM-5 criteria for OUD. Individuals in OUD recovery can be included in these studies. Individuals with physical dependence but who do not meet DSM-5 criteria for OUD are NOT a priority for this initiative. Key outcomes of interest relevant to OUD populations include treatment engagement and retention, remission, relapse, mortality, reduced opioid consumption, and other adverse health events. Applicants are encouraged to utilize the OUD Cascade of Care model to identify how their intervention may improve retention in the continuum of care. For research projects that focus on opioid misusing populations, the PI must justify the approach to measuring reductions in harmful behaviors associated with misuse. Of note, a singular measure of reduced opioid consumption indicated by decreased morphine in milligrams equivalents and/or days of opioid consumption is not a sufficient measurement of reduced opioid misuse.

CP CDEs: The HEAL Clinical Pain Common Data Element (CDE) Initiative provides an unprecedented opportunity for the pain research community to access quality and meaningful data across pain conditions, diverse populations, and multiple interventions. The HEAL CDE initiative aims to facilitate cross-study comparisons, improve interpretability of findings for patient-reported outcomes, and improves the ability to compare results across trials to quantify the impact of interventions. Research centers will be required to use the HEAL Clinical Pain Core CDEs which include measures within 9 pain domains and are specific to either adult or pediatric populations and acute or chronic pain conditions. The domains include pain intensity, pain interference, physical functioning/quality of life, sleep, pain catastrophizing, depression, anxiety, treatment satisfaction, and a substance use screener (CP Core CDEs). Studies that use additional pain screening tools must select from a comprehensive set coded through HEAL or submit their tools for coding to comply with HEAL pain data harmonization. Any outcome measures specific to CP should be validated measures appropriate for the pain condition.

Economic analysis: To ensure robust adoption of findings and implementation strategies, rigorous economic evaluations, especially cost-effectiveness analyses, such as those following the recommendations of the Second Panel on Cost-Effectiveness in Health and Medicine, are strongly recommended. Economic evaluations that consider relevant economic outcomes of proposed interventions from a societal perspective (e.g., that measure or model the actual or potential impact of specific interventions, approaches, or strategies on health-related behaviors, healthcare utilization, and health outcomes) are especially encouraged.

Encouraged Outcome Measures

Patient perspectives: Whenever possible, patient-centered and holistic outcomes related to the intervention are recommended to be collected as secondary measures, and should be informed by persons with lived experience (PWLE) engagement. Examination of the intervention on reducing stigma and health care disparities is also encouraged and likewise should be examined via engagement with key stakeholders to meaningfully address the health care environment. Additional information on PWLE and stakeholder engagement is provided below.

Additional Outcome measures: This solicitation encourages inclusive recruitment of subjects with common comorbidities, such as GAD, MDD, and AUD/heavy drinking, to address the needs of the whole patient. For interventions that do not intend to change GAD, MDD, and AUD outcomes, investigators are encouraged to measure any changes in these comorbidities as secondary measures. If the tested intervention is intended to also treat GAD, MDD, and AUD/heavy drinking in addition to CP and OUD, then outcomes associated with GAD, MDD, and AUD/heavy drinking should also be included as primary outcome measures.

PWLE and Stakeholder Engagement

Patients and other key stakeholder groups are the consumers of the interventions developed by NIH supported clinical trial research. Meaningful engagement and collaboration with these partners throughout the research process, including research design, conduct, and dissemination of study findings, have the potential to improve the quality of care, maximize implementation, and sustain utilization of these interventions. Hence, applications must include PWLE or members from patient advocacy groups and other stakeholders relevant to the research projects. In addition to informing the research design, applicants are strongly encouraged to utilize patient perspectives to inform subject recruitment, treatment retention, and engagement in follow-up care. Furthermore, applicants should include mixed methods approaches to documenting the patient journey in their treatment history and determine if these factors impact outcomes such as engagement and retention in care. Relevant stakeholders may include, but are not limited to payors, care takers, multidisciplinary health care providers, policymakers, advocacy groups, or professional organizations that create clinical care guidelines. Applicants should leverage these perspectives to inform best practices for disseminating research findings to target audiences.

Applications must include a minimum of 3 PWLE or patient organization representatives. There is no minimum requirement for the number of stakeholders included in the research team, but applicants must justify the diversity and selection of these stakeholders. It is expected that PWLE and stakeholders from each research center will form a trans-network workgroup and meet at least every 6 months.

Points to Consider Regarding Racial Diversity in Multidisciplinary Team Science: 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. Diverse teams of scientists will lead the way to develop more innovative inclusive research that will more broadly enhance public health. Fostering diversity by addressing underrepresentation in the scientific research workforce and health care system is a key component of the NIH strategy to identify, develop, support and maintain the quality of our scientific workforce. Therefore, applicants are strongly encouraged to include as research and healthcare staff, and key contributors, individuals who are underrepresented in biomedical research including individuals of diverse racial/ethnic, gender, rural and low-income backgrounds.

Points to Consider Regarding Early Stage Investigators: Pain treatment in individuals with OUD and other co-occurring substance use and psychiatric conditions 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 vulnerable populations in the future, applicants are strongly encouraged to indicate how they will include early stage investigators in this funding opportunity.

Special Considerations:

Applications with the following specifics will be considered non-responsive and will not be reviewed:

• Applications that do NOT measure BOTH non-cancer CP and OUD/misuse outcomes as primary measures. AUD/heavy drinking, MDD, and GAD outcomes are encouraged
• Applications that do not commit to collaborating across the network, including executive meeting and workgroup participation, data harmonization, and other activities of synergy
• Applications that do not include two-three research projects from the prioritized research clusters
• Applications that do not include a multisite design for integrated care models or implementation research clusters
• Applications that do not include plans for meaningful engagement with PWLE or representatives from patient advocacy groups and stakeholders relevant to the research project
• Research sites with communities outside the US and its territories
• PIs who do not commit at least 2.0 person months of effort to the application per year for the life of the award

On June 1-2, 2020, NIH held a workshop on Managing Chronic Pain in Individuals with Co-occurring OUD, and Other Psychiatric Conditions. A recording and summary of this meeting's proceedings are available at https://apps1.seiservices.com/HEALPainOUDWorkshop/Default.aspx. NIH issued a Notice of Intent to Publish a Funding Opportunity Announcement for Research Sites for the research centers (NOT-DA-20-071). Applicants are encouraged to participate in a future technical assistance webinar related to this FOA, which is anticipated to occur December 2020/January 2021. The date for this webinar will be published in a Notice associated with this RFA.

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 (http://ww2.drugabuse.gov/about/organization/nacda/points-to-consider.html) 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.

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

Section II. Award Information

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

Section III. Eligibility Information

1. Eligible Applicants

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Local Governments

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

Federal Governments

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

Other

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

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

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

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

Applicant organizations

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

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

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

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

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

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

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

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

The NIH will not accept duplicate or highly overlapping applications under review at the same time. 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 NOT-OD-11-101)

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

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: NIDALetterofIntent@mail.nih.gov.

Applicants are encouraged to send the letter of intent by email to the email address above but as an alternative the letter may also be sent to:

Office of Extramural Policy and Review
National Institute on Drug Abuse
3WFN 9th Floor, MSC 6021
301 North Stonestreet Ave
Bethesda, MD 20892

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

With the following additional requirements:

The Research Strategy must consist of the following sub-sections with the indicated page limits:

Sub-section A Research Site Overview, Management, and Operations (6 pages): required

Sub-section B Stakeholder Engagement and Outreach (6 pages): required

Sub-section C Research Project 1 (12 pages): required

Sub-section D Research Project 2 (12 pages): required

Sub-section E Research Project 3 (12 pages): optional

Sub-section F Data Collection, Management, and Harmonization (3 pages): required

Sub-section G Pilot projects (6 pages): optional

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.

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

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

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

With the following additional instructions:

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 nature, severity, and trends in OUD/misuse and CP for the targeted research sites. 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.

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 the network. Applicants should provide their ability to engage patients and stakeholders. Applicants should provide evidence of expertise in the conduct of clinical trials, particularly collaborative, pragmatic, randomized clinical trials. 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: participating in reviews of network publications, actively engaging in data harmonization efforts, making data from their study available to others, and engaging with the Coordination and Dissemination center on knowledge and product dissemination efforts. Participation in such network activities may be included among outcomes that may be tracked and reported to NIH by the Coordination and Dissemination center.

R&R Budget

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

With the following additional instructions:

In the budget justification, provide budget breakout for activities under each sub-section of the research strategy. Applicants are encouraged to include support for the PWLE/representatives from patient advocacy organizations and other relevant stakeholders. Budgetary support might include allowable salary support or honorarium, travel, and per diem costs. If applications have not predetermined PWLE and stakeholder representatives, 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. Applications must include a minimum of 3 PWLE and/or representatives from patient advocacy organizations.

Requirements for Participating in Network Activities

Budgets should include funds for travel for the PD(s)/PI(s), 1 stakeholder partner, 1 PWLE/patient organization representative, and up to three additional project staff to participate in in-person executive committee meetings once per year, every year of the award, in Rockville, MD. An additional in-person kickoff meeting to be held in Rockville, MD 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 executive committee meeting, representatives from each research center are expected to participate in virtual executive committee meetings that will occur quarterly. PI(s), 1 stakeholder partner, and 1 PWLE/patient organization representative should be present from each research center at these virtual meetings.

Stakeholder and PWLE partners from each research center will form a community workgroup to provide guidance on network activities. This group is expected to convene every 6 months. Time and support should be budgeted to participate in such activities.

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 (e.g., publication policy, data policy, stakeholder and patient engagement, biostatistics, and subject recruitment). Applicants will also be required to provide the 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. Time should be budgeted to participate in such activities.

At least 1 PI should also be present at the HEAL Investigators meeting that convenes annually. Awardees are expected to participate in break-out sessions with other HEAL programs of relevance to this initiative (e.g., PRISM, ERN, BACPAC, BRIM, etc.) at the annual HEAL Investigator meeting. Time and support should be budgeted to participate in such activities.

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

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

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

Specific Aims: A 1-page Specific Aims describing all of the subsections are required. Applications must include the following functional and structural units. These units referred to as Sub-sections A-G must be clearly marked and include all information specifically requested for each of them:

Sub-section A Research Site Overview, Management, and Operations : required

Sub-section B Stakeholder Engagement and Outreach: required

Sub-section C Research Project 1 : required

Sub-section D Research Project 2 : required

Sub-section E Research Project 3 : optional

Sub-section F Data Collection, Management, and Harmonization : required

Sub-section G Pilot projects : optional

Research Strategy:

Applicants are requested to develop and propose a research concept that lays out a theoretically grounded, hypothesis-driven, study design to address gaps in the continuum of care for individuals with comorbid OUD/misuse and CP. Each application must propose two-three distinct research projects with a unique clinical trial intervention that belong to the pre-specified research clusters. The research strategy section should be organized as follows:

Sub-section A Research Site Overview, Management, and Operations (): required

Applicants should demonstrate their experience in conducting similar studies. Each application must propose a plan for the leadership, coordination, administration, and organization of the application. This section should describe: a) the overall structure to promote interactions among sites and providers involved with the proposed research, relevant key stakeholders/PWLE identified in the proposed research, the Coordination and Dissemination Center, NIH stakeholders, and other funded research centers; b) administrative organization for the proposed center with qualifications, roles, responsibilities, and lines of authority for personnel involved in the collaborative grant; c) project management plans listing study deliverables and timelines, d) processes for monitoring, reporting, and achieving project goals; e) plans for quality control to ensure rapid problem identification and resolution, prioritization of resources, maintaining high quality data and publications; f) communication plan across the research sites, the NIH, other awarded research centers, and the Coordination and Dissemination Center. For multisite projects, include a conflict resolution plan among the site investigators. The proposed plan must commit to participating in in-person executive committee meetings once per year, every year of the award, in Rockville, MD, quarterly virtual meetings, and trans-HEAL work groups as appropriate to ensure dissemination of research findings, harmonization of data collection and analysis, best practices, etc. The proposed plan must include plans to interact with PIs from other HEAL programs of relevance to this initiative (e.g., PRISM, ERN, BACPAC, BRIM, etc.).

Sub-section B Stakeholder Engagement and Outreach : required

The application must include a plan for involving PWLE or representatives from patient organizations to capture their perspectives and serve as collaborators in the designing, conducting, and dissemination stages of the research projects. Additionally, non-patient stakeholders relevant to the project must also be included. Relevant stakeholders may include, but are not limited to payors, care takers, health care providers from diverse disciplines, policymakers, advocacy groups, and professional organizations that create clinical care guidelines. Applicants should leverage these perspectives to inform best practices for disseminating research findings to target audiences.

Applications must include a minimum of three PWLE/patient organization representatives. There is no minimum requirement for the number of stakeholders included in the research team, but applicants must justify the approach for active and sustained engagement with these partners. The application must also describe experience, expertise, and record of working with relevant stakeholders and PWLE and engaging them in meaningful and collaborative manner. There must be a plan to actively engage stakeholders/PWLE in all aspects of research, including research design, data collection and analysis, dissemination of findings to the appropriate audiences, subject recruitment, treatment retention, and engagement in follow-up care. Furthermore, applicants should include mixed methods approaches to document the patient care journey to determine which facilitators and barriers impact treatment outcomes like engagement, retention, and follow up in care. These activities will be executed through the establishment and regular meetings of a Stakeholder Consultation Board that includes PWLE. The application must include plans for developing the structure of, the role of, the expected contribution of the Stakeholder Consultation Board, and meeting frequency. Applicants must include plans for capturing the patient narrative and propose holistic outcome measures whenever possible. Applications must include plans for how stakeholders from the research center will interface with dissemination efforts executed by the Coordination and Dissemination Center. There should be plans for how stakeholder engagement will address stigma and health disparities as they relate to this complex patient population and health care systems.

Sub-section C Research Project 1 : required

Each application must propose two-three research projects from the high priority research clusters listed in the RFA. These clusters include (1) Effectiveness trials on integration of evidence-based interventions for CP and OUD/misuse to provide optimal approaches for treatment of both conditions; (2) Evaluation of Integrated Models of Care Delivery for evidence-based treatments for CP and OUD/misuse; (3) Implementation strategies to maximize reach and sustainability of integrated evidence-based practices for pain and OUD/misuse. Of note, for the Integrated Care Models research cluster, study designs must ensure coordinated and sustained linkage between CP and OUD specialists to provide meaningful and integrated care delivery for the patient. Study designs that propose referrals to a pain or OUD health care provider as a model of care are not appropriate for this FOA. For effectiveness trials, this FOA invites a wide range of treatment approaches ranging from pharmacological, behavioral, and/or medical devices (e.g., TMS) that have demonstrated efficacy for treating CP or OUD/misuse. The PI must provide supporting evidence to justify the selection of the intervention for treating both CP and OUD/misuse.

Applicants are NOT required to address all three research clusters. Applicants have the flexibility to select any combination of the high priority research clusters and may opt to execute all of the research projects within a single high priority research cluster. More important than any particular combination of clusters is the justification of the approach used based on supporting evidence and the potential for rapid and meaningful impact on patients and health care system practices. Applicants are encouraged to consider companion research approaches, such as modeling or other creative designs, that could generate results in advance of the clinical trial findings.

The research plan for each clinical trial project must be organized to include the following subsections: significance, innovation, preliminary data, approach, and alternate strategies. Embedded within these subsections, applicants should include details on the following:

1. A detailed description of the proposed research project, including a clear specification of the proposed health care systems and intervention.

2. A brief description of the proposed clinical research sites, including: (1) plans for ensuring high rates of recruitment and retention; (2) the justification of the selected number of sites including power analyses appropriate to the targeted outcomes and study design and (3) specifics regarding the demographic diversity of the expected study population. Please see notes below for additional guidance regarding proposed clinical research sites.

3. A description of the selection and justification of proposed clinical research sites for research clusters that require a multisite research design. Projects that examine integrated care models between CP and OUD services and projects that test different implementation strategies must propose a multisite research design. Projects that adapt evidenced-based interventions for treating CP or OUD to effectively treat both conditions do NOT have to meet a multi-site requirement, but applicants are encouraged to do so if it is feasible. For multisite projects, applicants are encouraged to consider low resourced settings, rural areas, and other areas with systemic challenges associated with treating CP and OUD when selecting the clinical research sites. Letters of Support and required details for each research site should be provided in the application. The following guidelines should be followed with respect to selecting clinical sites:

• Sites selected should consistently serve a high volume of patients with comorbid CP and OUD 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 this setting is expected to be a high impact setting from a public health perspective.
• Although some of the research clusters require a multisite research design, the proposed number of clinical performance sites should be justified scientifically based on power analyses appropriate to the design and outcomes of interest in the proposed study. In general, it is expected that applicants will be able to pre-specify their expected clinical research sites. If there is a compelling reason why this cannot or should not be done, applicants should provide similar details on the potential sites and what criteria will be used for selecting sites.
• Additional detail should be included on planned performance sites as detailed in the SF424(R&R) Project/Performance Site Locations.
• Applications that opt to include two research projects within one research cluster are encouraged to identify study designs that are synergistic. For example, the applicant may choose to use the same control sites across the two research projects.

4. Description of study outcomes on CP and OUD/opioid misuse as primary outcomes.

• OUD/opioid misuse CDEs: Subjects recruited for these studies must have non-cancer CP and meet the definition of opioid misuse or DSM-5 criteria for OUD. Individuals who are in OUD recovery can be included in the studies. Individuals with physical dependence but who do not meet DSM-5 criteria for OUD are NOT a priority for this initiative. Key outcomes of interest relevant to OUD populations include treatment engagement and retention, remission, relapse, mortality, reduced opioid consumption, and other adverse health events. Applicants are encouraged to utilize the OUD Cascade of Care model to identify how their intervention may improve retention in the continuum of care. For research projects that focus on opioid misusing populations, the PI must justify the approach to measuring reductions in harmful behaviors associated with misuse. Of note, a singular measure of reduced opioid consumption indicated by decreased morphine in milligrams equivalents and/or days of opioid consumption is not a sufficient measurement of reduced opioid misuse.
• CP CDEs: The HEAL Clinical Pain Common Data Element (CDE) Initiative provides an unprecedented opportunity for the pain research community to access quality and meaningful data across pain conditions, diverse populations, and multiple interventions. The HEAL CDE initiative aims to facilitate cross-study comparisons, improve interpretability of findings for patient-reported outcomes, and improves the ability to compare results across trials to quantify the impact of interventions. Research centers will be required to use the HEAL Clinical Pain Core CDEs which include measures within 9 pain domains and are specific to either adult or pediatric populations and acute or chronic pain conditions. The domains include pain intensity, pain interference, physical functioning/quality of life, sleep, pain catastrophizing, depression, anxiety, treatment satisfaction, and a substance use screener (CP Core CDEs). Studies that use additional pain screening tools must select from a comprehensive set coded through HEAL or submit their tools for coding to comply with HEAL pain data harmonization. Any outcome measures specific to CP should be validated measures appropriate for the pain condition.
• Describe a plan for collecting data on any other opioid-related secondary outcomes of the study, including but not limited to: patient satisfaction, stigma, component Patient-Reported Outcomes (PROs), quality of life, health disparities, and outcomes related to common psychiatric comorbidities (AUD/heavy drinking, MDD, and GAD).

5. A strong justification for the selected follow-up period. Research designs should include a follow-up period of 6 months and ideally, up to a year.

6. The approach to develop and collect data needed to address health economics questions related to incremental cost, cost effectiveness, economic modeling, and sustainability. Rigorous economic evaluations, especially cost-effectiveness analyses are strongly recommended. Economic evaluations that consider relevant economic outcomes of proposed interventions from a societal perspective (e.g., that measure or model the actual or potential impact of specific interventions, approaches, or strategies on health-related behaviors, healthcare utilization, and health outcomes) are especially encouraged.

7. Potential sustainability of the proposed intervention. The research project should be of sufficient priority to identified stakeholders such that the potential for positive findings from the study is apparent and can be sustainably incorporated into standard practice after the study concludes.

Sub-section D Research Project 2: required

Details from Sub-section C apply to Sub-section D.

Sub-section E Research Project 3 : optional

Applicants have the option to include a third research project. Details from Sub-section C apply to Sub-section E.

Sub-section F Data Collection, Management, and Harmonization: required

Describe the plan for data collection, management, quality control, integration and any harmonization across common data elements for the research sites and the approach to dealing with these issues between research sites, including data sharing. Applicants must provide a commitment to harmonizing CDEs with awarded research centers within the IMPOWR network and awardees from NOT-21-005. These efforts will occur during an in-person data harmonization meeting that will convene in the Fall of 2021, prior to study protocol launch. Applicants must comply with the HEAL data sharing policy.

Describe a plan for collecting high quality data for the primary outcomes of OUD/misuse and CP and any data outcomes as they relate to changes in AUD, MDD, and GAD treatment. Applicants will be required to use the HEAL CP Core CDEs which include measures within 9 pain domains and are specific to either adult or pediatric populations and acute or chronic pain conditions. The domains include pain intensity, pain interference, physical functioning/quality of life, sleep, pain catastrophizing, depression, anxiety, treatment satisfaction, and a substance use screener. Studies that use additional pain screening tools must select from a comprehensive set coded through HEAL or submit their tools for coding to comply with HEAL pain data harmonization. Any outcome measures specific to CP should be validated measures appropriate for the pain condition.

Of note, a single composite holistic outcome measure for CP and OUD will be developed by the IMPOWR Coordination and Dissemination Center in collaboration with the awarded research centers and through PWLE engagement. Research centers must use this tool whenever it becomes available to the network and applications must reference commitment to using this newly developed screening tool.

Applicants must provide a commitment to provide the 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. To this end, applicants should detail the data platform and provide a plan on how data will be shared (i.e. format, frequency of updates, what type of data, level of data detail). If multiple organizations will collaborate as part of the proposed application, a plan for collaboration within the program must be presented as well.

Sub-section G Pilot projects : optional

Applicants will have the option to include pilot projects, but these do not count toward the required two-three research projects. At minimum, two research projects must be active at all times. Pilot projects may be used for new, early stage or independent investigators and should represent innovative studies to develop and explore new activities or directions or take advantage of special opportunities. Pilot projects may be research and development pilots, feasibility studies, or other pilot work broadly defined as foundation work for further research. Pilot projects may not be used to supplement or prolong ongoing research and should not be used as bridge funds when other research support is no longer available. Pilot projects do not have to involve a clinical trial. Pilot project ideas can extend beyond the high priority research clusters identified in the RFA, but must be concentrated on CP and OUD/misuse.

The support for individual pilot project studies is typically of relatively short duration (e.g., 1-2 years), depending upon the nature of the research. Applicants may propose and request funding in the first year for specific, already conceptualized pilot projects, as well as for pilot projects to be added in subsequent years of the project. Applications requesting support for pilot projects must describe a process for within-program scientific review of new pilot projects to be initiated in future years of the project, and a process for evaluating ongoing pilot projects for adequate progress. Pilot projects presented in the application will be reviewed as part of the assessment of scientific and technical merit of the application, and as examples of the kinds of pilot projects that the overall program might initiate in the future as a result of its internal review process.

For all pilot projects, describe the internal institutional plans and procedures to ensure that all projects supported from this award will comply fully with all applicable Federal regulations, policies, and guidelines for research involving human subjects, including the evaluation of risks and protections in project proposals, appropriate ethical oversight of funded projects, and plans for data and safety monitoring for clinical trials, if applicable.

Letters of support:

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

The following letters of support are encouraged, but not required, to demonstrate participation from partners at multiple levels:

1) Letters from stakeholders relevant to the research projects. A list of suggested stakeholders is outlined in Part 2, Section I of this announcement.

2) A minimum of three letters are required from representatives from patient organizations and/or PWLE. 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.

The following modifications also apply:

All applications, should provide a plan for sharing data with other research sites within the application, and across awarded research centers.

All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

HEAL Central Data Sharing Platform Requirements

The award recipient and its collaborators must comply with all NIH HEAL Initiative Data Sharing policies established during the project period. This includes compliance with the NIH HEAL Initiative central data platform requirements and timelines developed through the HEAL consortium. It is expected that all data collected by award recipients and their collaborators, as part of the NIH HEAL Initiative, will be shared with the NIH HEAL Initiative central data platform.

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

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

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

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

Study Record: PHS Human Subjects and Clinical Trials Information

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

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

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

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

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

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

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

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

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

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

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

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

Important reminders:

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

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

See more tips for avoiding common errors.

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

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

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).

While each application will be evaluated in its entirety based on one overall impact score per application, the three research projects within each application will also each receive a separate impact score.

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 generate novel information for improving collaborations between pain and OUD clinicians to improve public health outcomes? Does the application include plans to effectively disseminate information to relevant audience and engage stakeholders/PWLE in a meaningful manner? If appropriate, does the application address plans to reduce stigma for OUD and CP both within the healthcare system and beyond and attend to barriers in health equity?

In addition, for applications involving clinical trials:

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

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? Are PWLE/patient organizations representatives and stakeholders appropriately represented on the application and is the extent of engagement proposed adequate for the proposed work? Are researchers with expertise in pain treatment, public health and healthcare data systems, data harmonization and integration, health services research, OUD treatment research, health economics, and other expertise specific to the intervention design part of the application? Are the proposed investigators established in their respective areas of research and/or administration, and will their collective experience as a team ensure appropriate oversight and execution of the research? Is there a commitment to promoting early stage investigators and diversity (e.g., racial, ethnic, gender, individuals with disability) among the investigative team?

In addition, for applications involving clinical trials:

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

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: Is there innovation in the approach to developing a tailored intervention to meet the unique needs of individuals with CP and OUD? Are there innovative approaches to engaging with PWLE/patient organization representatives and key stakeholders in a meaningful manner?

In addition, for applications involving clinical trials:

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

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?

Specific to this FOA: Does the application foster innovative, multidisciplinary, team science approaches across specialties to identify appropriate treatment interventions, and measure outcomes of relevance to the patient population (e.g., assess both holistic and component outcomes)? For effectiveness study designs, does the PI provide a strong justification for the selected treatment approach? Is a strong justification provided for selecting the health care settings? Does the study power account for the RFA-specified primary and secondary outcomes? If the application proposes to evaluate opioid misuse, does the PI justify the proposed outcomes to measure a reduction in misuse that isn't a reduction in MMEs and/or days of opioid consumption? If the proposed intervention aims to treat AUD, MDD, and/or GAD, does the proposed approach address the unique needs of this population? Does the application consider a broad spectrum of secondary outcomes that are directly related to the RFA-specified patient population? When appropriate, is there a thorough approach to participating in the economic research to ensure adoption? Is there a clear conceptual framework for working with stakeholders to help the team develop a data-driven tailored response to the opioid and pain crisis? Does this design test interventions or strategies that are potentially generalizable to other communities or settings? Does this design test a practice or intervention that is widespread, but for which limited evidence is available? Are plans for data collection, harmonization, management, quality control, and sharing appropriate and adequate for the proposed work? Is the proposed organizational structure appropriate for managing the activities of the research center? Are the proposed plans adequate for tracking project activities and monitoring progress, timelines and budgets, including project plan controls to keep multiple project tasks on time and on budget? Is there a clear plan for communications among the involved key personnel, with research sites, the Coordination and Dissemination Center, other funded research centers, NIH staff, and other participating entities? Is there a plan to complete data analysis within the proposed period of the award? Is there a clear plan to work with PWLEs and stakeholders on research design and dissemination of study findings? Is there a clear commitment to participate in synergistic activities including executive meetings, workgroups, meetings with HEAL PIs who oversee projects of relevance to this initiative, and data harmonization? 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?

In addition, for applications involving clinical trials:

Does the application adequately address the following, if applicable

Study Design

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

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

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

Data Management and Statistical Analysis

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

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?

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 necessary to deliver evidence-based treatment interventions?

In addition, for applications involving clinical trials:

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

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

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

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

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

Specific to applications involving clinical trials:

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

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

Protections for Human Subjects

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

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

Inclusion of Women, Minorities, and Individuals Across the Lifespan

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

Vertebrate Animals

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

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) Data Sharing Plan; (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 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.

• 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

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

Section VI. Award Administration Information

1. Award Notices

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 grantee’s business official.

Awardees 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: Grantee 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 awardee 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).

Institutional Review Board or Independent Ethics Committee Approval: Grantee institutions must ensure that protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the awardee must provide NIH copies of documents related to all major changes in the status of ongoing protocols.

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, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

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

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

• Recipients of FFA must ensure that their programs are accessible to persons with limited English proficiency. HHS provides guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/fact-sheet-guidance/index.html and https://www.lep.gov. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at https://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

• Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html.

• HHS funded health and education programs must be administered in an environment free of sexual harassment. Please see https://www.hhs.gov/civil-rights/for-individuals/sex-discrimination/index.html; https://www2.ed.gov/about/offices/list/ocr/docs/shguide.html; and https://www.eeoc.gov/eeoc/publications/upload/fs-sex.pdf. For information about NIH's commitment to supporting a safe and respectful work environment, who to contact with questions or concerns, and what NIH's expectations are for institutions and the individuals supported on NIH-funded awards, please see https://grants.nih.gov/grants/policy/harassment.htm.

• Recipients of FFA must also administer their programs in compliance with applicable federal religious nondiscrimination laws and applicable federal conscience protection and associated anti-discrimination laws. Collectively, these laws prohibit exclusion, adverse treatment, coercion, or other discrimination against persons or entities on the basis of their consciences, religious beliefs, or moral convictions. Please see https://www.hhs.gov/conscience/conscience-protections/index.html and https://www.hhs.gov/conscience/religious-freedom/index.html.

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

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

Not Applicable

3. Reporting

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.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees 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.

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

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

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

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

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

Maribeth Champoux, Ph.D.
Center for Scientific Review
Telephone: 301-594-3163
Email: champoum@mail.nih.gov

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

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.