It is critical that applicants follow 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 the 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 1. Overview Information
Part 2. Full Text of the Announcement

Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

Background

There is an opioid crisis in the United States. More than 4 million people in the United States report using opioids for non-medical purposes in the past month, and almost 2 million report symptoms consistent with an opioid use disorder (OUD) (National Survey on Drug Use and Health [NSDUH]). Fewer than half of those with an OUD receive treatment and even fewer receive treatment of adequate duration. The number of drug overdose deaths involving opioids has quadrupled between 1999 and 2015, to more than 33,000 annually (Rudd et al., 2016).

Although there are safe and effective FDA-approved pharmacotherapies for OUD (e.g., buprenorphine, and methadone), relapse prevention of OUD (e.g., depot naltrexone), opioid withdrawal (e.g., lofexidine), and opioid overdose (e.g., naloxone), their outcomes are less than optimal. There are multiple factors associated with these suboptimal outcomes. Some social and behavioral interventions have shown scientific evidence of efficacy in the treatment of OUD but not used as an adjunct to MAT. However, these interventions are not widely utilized. This may be, in part, due to many of these behavioral/social interventions not having been systematically studied in conjunction with different clinical targets of OUD pharmacotherapies. For example, although depot naltrexone is safe and effective for relapse prevention of OUD, there are no psychosocial interventions that have been methodically evaluated to determine whether they would improve long-term outcomes to reduce substance abuse relapse. Similarly, lofexidine was recently approved for the treatment of opioid withdrawal but there are no studies that have evaluated whether adding brief (<2 weeks) behavioral/social interventions, that when used in tandem with lofexidine could manage opioid withdrawal symptoms and drug craving, which could lead to positive long-term outcomes, such as sustained abstinence. There is significant clinical evidence that pharmacotherapy can be more effective when combined with behavioral/social interventions in other areas such as smoking cessation. However, the evidence for the effectiveness of these interventions combined with OUD pharmacotherapy is insufficient. At the same time, the labeling for these pharmacotherapies include a recommendation that patients also receive psychosocial interventions. Therefore, there is an urgent need to evaluate if psychosocial interventions can improve adherence of MAT for OUD and, at the same time, enhance the treatment intervention and long-term outcomes, including a reduction in drug abuse relapse.

Adherence

Adherence is increasingly understood as a multifaceted concept. Adherence to MAT involves three dimensions: initiation (i.e., starting the MAT regimen), implementation (i.e., executing the MAT dosing schedule), and persistence (i.e., length of time on MAT before discontinuation). Each dimension of adherence may have unique determinants, and each may require distinct behavioral and social interventions. Additionally, for many OUD patients MAT is part of a treatment regimen, which may include inpatient or outpatient substance abuse treatment, social supports such as 12-step programs, or professional therapy. Persons with OUD often experience multiple comorbid conditions which may require different and concurrent courses of therapy, or present unique cognitive, emotional, or social challenges that can interfere with adherence.

Adherence to MAT and other OUD treatments is dynamic with the potential to change over time. Some health care professionals and researchers may view adherence as a stable and dichotomous property of individuals; i.e., "there are adherent patients, and there are non-adherent patients." This misses how adherence to MAT may vary in response to disease activity, treatment methods, and the course of psychosocial or illness comorbidities. The dynamic nature of adherence underscores the challenges of improving adherence to MAT over the course of care. This is also an opportunity to re-examine and/or adapt evidence-based behavioral and social interventions that have not previously been used to support MAT adherence.

Determinants of adherence and non-adherence span a broad ecologic spectrum. They may be influenced by the severity of addiction; the complexity of MAT combined with concomitant treatments; stigma associated with OUD; individual factors such as sociodemographic characteristics, comorbidities, cognitive functioning, mental health status, health literacy, self-efficacy and motivation for self-management; aspects of the person-provider relationship; social and factors such as an individual’s access to social support, relationships and gender dynamics, and culture; and successively larger structural influences, including factors related to health economics (MAT cost, insurance coverage, access to transportation, and cost-sharing) and the characteristics of MAT delivery approaches. These multilevel adherence determinants invite a range of interventions that target individuals, families, caregivers, health-care providers, communities, and/or healthcare system delivery methods.

New developments and innovations provide opportunities to advance MAT adherence research. Advances in mobile health (mHealth) technologies and informatics provide opportunities to monitor MAT adherence, improve measurement precision, and to deliver individualized interventions that are timely, tailored, and interactive. Attention to patient-centered care and shared decision-making models that include the person, family, and caregiver as part of the care team further broadens targets for improving adherence. Growing attention to health behavioral economic approaches suggest new ways to "nudge" behavior in helpful directions. Additionally, healthcare coverage models that are designed to incentivize the delivery of high-quality and cost-efficient care are becoming increasingly common.

Regardless of focus or approach, the MAT adherence research will benefit from high scientific rigor and innovative study designs. A Cochrane review of randomized controlled trials of medication adherence interventions in 2014 found many trials were compromised by low statistical power and/or biases resulting from use of self-reported adherence measures when trial participants were not blinded to treatment allocation. Applications submitted in response to this FOA are encouraged to propose well-powered trials with appropriate sample sizes that employ and describe objective measures, centralized randomization procedures, and blinded outcome assessors. Applications that propose novel research designs, including sequential randomized designs are also encouraged.

Chronic Pain

Chronic pain is an important co-morbidity in patients with OUD. Twenty to 30 percent of US adults report chronic pain . Treatment of acute and chronic pain conditions with opioids is contributing to the OUD epidemic. Pain patients at increased risk of developing OUD are those with pain that is inadequately controlled, exposed to opioids during acute pain episodes, and/or chronic pain in patients with a history of substance abuse. Among patients with OUD treatment and chronic pain, barriers to patients actively engaging in treatment include fear of inadequately treated pain and depression. A number of behavioral interventions have shown value for management of chronic pain. Recent American College of Physician guidelines for management of chronic back pain include recommendations to consider interventions including mindfulness-based stress reduction, multidisciplinary rehabilitation, meditative exercise such as tai chi and yoga, progressive relaxation, operant therapy and cognitive behavioral therapy (CBT). Additionally, a recent systematic review on Noninvasive Nonpharmacological Treatment for Chronic Pain from the Agency for Research on Quality and Health (AHRQ) concluded, "Exercise, multidisciplinary rehabilitation, acupuncture, CBT, and mind-body practices were most consistently associated with durable slight to moderate improvements in function and pain for specific chronic pain conditions." However, there are relatively few studies evaluating effectiveness of these nonpharmacologic interventions when used to treat the comorbidity of OUD and chronic pain.

Research Goals

The goal of this FOA is to solicit applications proposing to test approaches using behavioral and/or social interventions to improve adherence to MAT for OUD and, at the same time, may provide additional therapeutic benefit to improve long-term outcomes such as stress reduction, and opioid abstinence. Projects are strongly encouraged to leverage funding which individual U.S. states receive under SAMHSA awards in the last few years to enhance OUD treatment. A primary goal of this FOA is to encourage studies evaluating whether behavioral and/or social interventions may improve uptake or adherence to MAT, relapse prevention for OUD, or improve abstinence for persons engaged in OUD treatment.

The proposed projects must meet the following criteria:

• Project teams must include relevant stakeholders as key personnel or other staff on the project to ensure adequate input to study design and planned outcomes. For example, a project that proposes to integrate an intervention into a healthcare system must include a representative from that healthcare system as key personnel or other staff.
• Projects must be designed to generate causal inferences on the effects of behavioral/social approaches as an adjunct to MAT using FDA-approved medications for treatment of OUD, or prevent OUD relapse to reduce: drug use and/or overdose deaths, length of time on medication, dropout, time to relapse.
• Designs may include: observational studies, randomized controlled explanatory trials, randomized controlled pragmatic trials, or other types of controlled designs employing statistical approaches that mitigate bias and support causal inferences. Hybrid effectiveness-implementation designs may also be appropriate. Projects may incorporate randomization approaches appropriate to the research question, such as by cluster or timing of implementation. If another method is used to generate the comparison group, perhaps by staged assignment or staged implementation of the approach, it should provide comparable rigor to randomization. Randomization may occur at the patient, provider, clinic, or community level, as is appropriate to the research question.
• PDs/PIs are expected to attend an annual meeting of investigators funded under the FOA and engage in other activities, such as periodic conference calls, designed to facilitate appropriate standardization of measures, collaboration and other mechanisms for maximizing the scientific yield from this FOA.

Applicants proposing cluster-randomized trials are encouraged to consult relevant guidance documents issued by the NIH Health Care Systems Research Collaboratory:(http://rethinkingclinicaltrials.org/experimental-designs-randomization-schemes-top/experimental-designs-and-randomization-schemes-introduction/). Applications proposing observational studies should employ strong statistical methods designed to mitigate bias and support causal inferences.

Research topics (scientific questions of interest) may include, but are not limited to, the following:

• What is the effectiveness of integrated treatments as an adjunct to MAT versus MAT alone for persons with chronic pain and OUD?
• What are effective implementation strategies to engage patients, providers, healthcare systems, and communities to increase use of effective behavioral and/or social interventions as an adjunct to MAT to sustain benefits?
• Do behavioral therapies in combination with MAT reduce relapse rates for patients and prevent recurrence of opioid misuse?
• What impact does high adherence to a behavioral or social intervention have on adherence to MAT?
• Does improving patient and provider shared decision making in pain care treatments lead to better adherence to MAT or OUD relapse rates?
• Do specific settings (residential treatment, outpatient, intensive inpatient, community centers,
• telehealth, etc.) for delivery of behavioral interventions provide better outcomes? Is it better to have single provider or multiple providers? What type(s) of provider(s) delivers a given treatment more effectively?
• What are the incremental benefits of combined approaches relative to a single approach as an adjunct to MAT (e.g., psychological/behavioral [P/B] alone vs. P/B + physical activity [yoga, tai chi, or exercise] to treat pain)?
• What characteristics predict better response or adherence to MAT for patients (comorbidity, psychological characteristics, physical limitations), providers (training/education, certifications, experience treating OUD), communities (social supports, treatment resources, stigma), and healthcare systems (access to care, reimbursement)?

The R61 Phase

The primary objective of the R61 phase supported under this FOA is to perform the formative work necessary to prepare for a successful R33 phase. This may include adaptation and tailoring of interventions for the proposed R33, stakeholder interviews, focus groups, tests of feasibility and acceptability. Applicants are expected to provide a detailed description of the intervention(s) they propose to study. Applicants are also expected to provide detailed descriptions of the measures and a strong rationale for choosing such measures.

Milestones

Utilization of milestones is a key characteristic of this FOA. A milestone is defined as a scheduled event in the project timeline, signifying the completion of a major project stage or activity. Plans must be guided by milestones that will be reached by the end of the R61 phase. Milestones are to be performance-based to achieve completion of the study on time and on budget. The individual milestones must be quantifiable and measurable. A summary of the milestones will undergo an administrative review by the administering NIH Institute/Center (I/C) to ascertain if each milestone proposed was or was not met. Only R61 projects that have met milestones will be deemed eligible to transition to the R33 phase.

Funding for and transition to the R33 phase is contingent on the following: 1) meeting the milestones articulated in the R61 phase, 2) the availability of funds, 3) continued relevance of the research to the NIH and I/C missions, and 4) NIH and regulatory approval of the planned R33 activities (e.g., study documents, IRB).

Please note: To transition from the R61 phase to the R33 phase, grantees will submit a transition request 3 months prior to the proposed transition date. Successful achievement of milestones must be documented prior to submission of the transition package.

The R33 Phase

The primary objective of the R33 phase is the execution of the research study refined during the R61 phase.

Clinical Trials Not Responsive to this FOA

Applications proposing the following types of activities will be deemed non-responsive and withdrawn without review:

• Phase I (first-in-human) trials whether single or multi-site
• Studies to understand the mechanism of the intervention
• Drug or device safety trials
• Observational studies that are purely descriptive and do not use methods to mitigate bias
• Applications proposing to study botanical products or non-FDA approved medications

Considerations for Selection of Study Design

For interventions that either are or can be delivered in groups, investigators should have a strong rationale for the choice among trial designs options. The selection of study design should be guided by decisions about how best to deliver the intervention and by concerns regarding contamination and logistics.

In traditional randomized clinical trials (RCTs), individual participants are randomized to receive an intervention that is delivered individually (e.g. spinal manipulation, acupuncture, contingency management, individual behavioral therapy, or individually delivered hypnosis). When an intervention can be delivered in a group format there are several methods of randomizing participants to the intervention. The first option is an individually randomized group treatment trial (IRGTs), where individual participants are randomized to one of the interventions, but the intervention is delivered in small groups (e.g. group counseling, yoga, group-delivered Mindfulness Based Stress Reduction, or tai chi classes). The second option is a group-randomized trial (GRTs), also called cluster-randomized trial (cRCTs), where groups of participants are randomized to study conditions, often defined by their workplace, school, health care provider, or community. In cRCTs, the intervention provided to the randomized groups can be delivered individually, in small groups, or to the entire group.

The study team biostatistician will need to consider how the chosen study design led to the proposed data analysis and sample size estimates. The justification should include consideration of the positive intra-class correlation expected in data obtained from participants in the same groups, or clusters. In general, these types of studies need to consider how the data analysis and sample size address the extra variation expected in the data and the degrees of freedom available to estimate that extra variation. Failure to account for this variable in the sample size calculation can result in underpowered studies. Link to Office of Disease Prevention website on group and pragmatic randomized trials free online training is available (https://prevention.nih.gov/resources-for-researchers/nih-methods-training/grt)

Information Relevant to Specific Institutes/Centers:

In addition to the above description of the scientific objectives, resources communicating scientific interests of selected NIH I/C's are summarized below. Applicants are encouraged to contact the Scientific/Research contact of the intended I/C to ensure that the aims of the proposed project are consistent with I/C mission.

National Center for Complementary and Integrative Health (NCCIH)

The mission of NCCIH is to define, through rigorous scientific investigation, the usefulness and safety of complementary and integrative health interventions and their roles in improving health and health care. in the context of this FOA, NCCIH is particularly interested in encouraging applications that use complementary and integrative approaches to improve adherence to MAT. NCCIH is also interested in studies that will evaluate the impact of adding evidence-based complementary approaches for conditions that are commonly comorbid with OUD, such as pain or sleep disorders, to determine if they have a measurable impact on improving OUD outcomes. Applicants are encouraged to discuss applications the NCCIH contact listed in Section VII. Agency Contacts.

National Institute on Drug Abuse (NIDA)

The mission of NIDA is to advance the science on the causes and consequences of drug use and addiction and to apply that knowledge to improve individual and public health. In addition to supporting and conducting basic and clinical research, it also seeks to ensure the effective translation, implementation, and dissemination of scientific research findings to improve the prevention and treatment of substance use disorders. In the context of this FOA, NIDA’s Division of Therapeutics and Medical Consequences is particularly interested in the development of efficacious treatments for substance use disorders that are implementable and self-sustaining, as well as optimal behavioral strategies to promote medication adherence and improve outcomes of pharmacotherapies. Equally important to NIDA is behavioral intervention and health services research on the effectiveness, outcomes, hybrid effectiveness/implementation, or implementation studies of efficacious or effective interventions, be they behavioral, social, delivery, or economic, that improve persistence to OUD pharmacotherapy. A secondary interest would be the same types of studies of interventions that address issues on the part of clinicians, providers, health systems, or insurers that lead them to either not offer/reimburse for pharmacotherapy for OUD or to offer/reimburse it for a limited duration.

National Institute on Alcohol Abuse and Alcoholism (NIAAA)

The mission of the National Institute on Alcohol Abuse and Alcoholism is to generate and disseminate fundamental knowledge about the effects of alcohol on health and well-being, and apply that knowledge to improve diagnosis, prevention, and treatment of alcohol-related problems, including alcohol use disorder, across the lifespan. For the current FOA, NIAAA encourages research that seeks to evaluate mechanisms of behavior change among empirically-supported behavioral treatments that improve MAT adherence among individuals with co-occurring alcohol use disorder (AUD) and opiate use disorder (OUD).

National Institute on Aging (NIA)

NIA is interested in the effects of behavioral interventions on MAT in individuals in mid-life and older. Applicants should note that when proposing an effectiveness study of an efficacious behavioral intervention, issues of real-world training procedures, fidelity of delivery, and scalability may be addressed in the R61 phase. NIA applicants are referred to the NIH Stage Model (https://www.nia.nih.gov/research/dbsr/stage-model-behavioral-intervention-development), if proposing a (Stage IV) effectiveness study through this FOA.

National Institute on Minority Health and Health Disparities (NIMHD)

The mission of the National Institute on Minority Health and Health Disparities (NIMHD) is to lead scientific research to improve minority health and reduce health disparities. In the context of this FOA, NIMHD is particularly interested in supporting applications that focus on improving adherence to MAT and understanding determinants of adherence and non-adherence among minority groups and other health disparity populations disproportionately affected by the OUD epidemic. NIMHD is also interested in understanding variation in MAT initiation, implementation, and persistence by different minority and health disparity groups and understanding and reducing disparities. In addition, NIMHD seeks to identify multi-level intervention strategies for addressing MAT adherence. Applicants are encouraged to discuss applications with the NIMHD contact listed in Section VII. Agency Contacts.

Office of Behavioral and Social Science Research (OBSSR)

OBSSR does not award grants directly. PDs/PIs interested in proposing research projects should first contact an IC-based program director, as their application must be within the mission of one of the Institutes/Centers participating in this FOA. Applications that address questions raised during the HEAL Initiative meeting on social and behavioral contributions are relevant for this FOA:

• Which treatment strategies in which dosages and durations facilitate maintenance of initial treatment effects?
• Digital technologies can increase access and reach of OUD and chronic pain treatments, but which components of these treatments can be automated or delivered digitally without compromising effectiveness?
• How can extant knowledge on stigma in other disease contexts be applied to reducing stigma from OUD and encouraging treatment seeking of those with OUD, especially in communities with heightened levels of addiction stigma?
• What programs and policies effectively divert OUD individuals from the criminal justice system to the public health system and minimize the social and economic repercussions of a felony conviction that can contribute to relapse?
• What combination of programs and resources will give criminal justice systems the tools they need to address the large number of OUD and other substance abuse and mental health disordered individuals in the system or post-incarceration?
• Which models of integration are most appropriate for which types of healthcare and public health systems and settings?

National Institute of Mental Health (NIMH)

The National Institute of Mental Health (NIMH) has interest in research to improve adherence to MAT for people with co-occurring mental health conditions--to include elevated risk for suicide--and OUDs. NIMH is interested in research on adherence interventions that support the NIMH Strategic Plan for Research. All applications that propose clinical trials to test adherence strategies must follow the NIMH’s experimental therapeutics approach to intervention development and testing. For nonclinical trial research, NIMH has interest in research that examines mutable patient, provider, organizational, and policy-level factors that have the potential to serve as targets for future interventions to improve adherence to MAT for people with co-occurring mental health conditions.

• Examples of relevant research projects include but are not limited to the following: adherence interventions capitalizing on innovations in technology, consistent with NOT-MH-18-031; applications that use existing patient-level data, such as electronic medical records and prescription refill data, to support MAT adherence; adherence approaches to reduce empirically documented disparities in care and outcomes for racial and ethnic minorities and other underserved groups; adherence interventions that support shared decision making and patient engagement; adherence strategies that fit seamlessly into settings where MAT is or could be delivered to people with co-occurring mental health conditions (e.g., primary care, criminal justice, and community based outpatient clinics).
• Clinical trial and nonclinical trial adherence research that does not attend to mutable factors (i.e., mediators and targets) will be deemed low priority.

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

The mission of NICHD is to ensure that every person is born healthy and wanted, that women suffer no harmful effects from reproductive processes, and that all children have the chance to achieve their full potential for healthy and productive lives. The Institute also aims to ensure the health, productivity, independence, and well-being of people through optimal rehabilitation. For the current FOA, NICHD is particularly interested in applications focused on understanding and promoting adherence in several populations of interest who have OUD. This includes adolescents and young adults, women who are pregnant or postpartum as well as women with OUD resulting from gynecologic pain. More information about NICHD and the NICHD s National Center for Medical Rehabilitation Research is available at https://www.nichd.nih.gov/about/org/der/branches and https://www.nichd.nih.gov/about/org/ncmrr

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

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

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)

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)
• 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.

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

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).

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.

It is critical that applicants follow the Research (R) Instructions in the SF424 (R&R) Application Guide, except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:

• Descriptive title of proposed activity
• Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
• Names of other key personnel
• Participating institution(s)
• Number and title of this funding opportunity

The letter of intent should be sent to:

Martina Schmidt, PhD
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-594-3456
Email: [email protected]

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

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

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.

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

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

Specific Aims:

In the single page attachment allowed for the specific aims, applicants should include clearly marked headers for R61 Specific Aims and R33 Specific Aims with brief descriptions of key hypotheses.

Research Strategy:

The Research Strategy should be organized in a manner that will facilitate peer review. The body of the application should present an overview of the state of the science, current status and relevance of the trial, a discussion of the specific protocol, and the approach to data collection, analysis, and dissemination. The application should contain separate Approach sections for the R61 and R33 phases.

Separate, Significance and Innovation sections may be included, but they could also be combined into a single section within the R61 section as appropriate. It is not necessary to repeat any information or details in the R33 section that are described in the R61 section.

The following criteria should be addressed:

Significance: The significance of the proposed study and importance of the question should be clearly stated. If available, the application should provide rigorous preclinical or clinical preliminary data to support the study rationale. It is particularly important that there be a discussion of how the trial will test the proposed hypotheses and why there is clinical equipoise. The application should make clear the need for and timeliness of the study with emphasis on how the results will address an evidence gap and therefore advance our knowledge of theory and practice in this area. A discussion of the costs and benefits of the study should be included for evaluation of the trial's significance. The applicant is expected to provide a precise response to these two questions: Will the results be informative about the potential role of this treatment for prevention or treatment of OUD? How will the results effect future care in the state where the research is conducted?

Innovation: Explain how the application challenges and seeks to shift current research or clinical practice paradigms.

Approach: The research approach section should include a description of the supporting data, clinical trial experience, the experimental approach, and reference the Timeline and Milestone Plan.

Supporting Data: The studies that led to the proposed study should be presented. Data from pilot studies which show the need for and the feasibility of the trial should also be presented. Additional supporting data from other research should be included so that the approach chosen is clearly justified and adequately framed. The application should provide data which should demonstrate the plans for and the initial planning phase of the proposed early phase study (R61). Applications should address the rationale for choosing the planned specific behavioral intervention or approach. This may include public health impact if subsequent efficacy trials are conducted and positive; ethical dimensions; and/or patient perspectives on acceptability of the proposed intervention. Characteristics of any preliminary research results provided in support of the proposed project, whether conducted by the applicant or others, should be described in the application

Experimental Approach: The proposed experimental approach should include an appropriate study design and the rationale for the design chosen. The following elements should be included as part of the PHS Human Subjects/Clinical Trials Information forms as indicated or within the research strategy, but not in both sections. The experimental approach description should include:

• A brief description of the project timeline referencing but not repeating the required attachment for Timeline and Milestone Plan as appropriate.
• A description and rationale for the research hypothesis(es), methods of randomization if applicable, primary and secondary outcome measures, intervention(s), and participant follow-up procedures.
• A description of the study population and why it is the most appropriate group to answer the question, and how or if results will generalize to a broader population.
• For the R33 phase, describe the methodology including: a) the scientific rationale for the measure(s) used to assess the impact of the behavioral/social intervention; b) the measure(s) proposed to assess the interventions effect on MAT adherence and OUD. Information on measurement validity and reliability should be included in the application. Describe measurement schedules. The approach should be summarized clearly in the application.
• Discussion of the challenges expected in implementing the research and how these might be overcome.
• A discussion of potential challenges in implementing the research protocol and how they will be addressed.
• The strategy for timely publication and dissemination of results

Data Management and Quality Control: Details of efficient data management and methods for monitoring quality; Statistical Methods: Discussion of sample size justification to be powered on changes expected in the effect size expected for primary outcome measure; study outcome measures; plans for interim (if any, with cogent justification) and final analyses powered to detect impact on each aim; methods of bias control (e.g. use of health education arm); and methods for handling missing data.

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, with the following modification:

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

Appendix:

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

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

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

Study Record: PHS Human Subjects and Clinical Trials Information

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

Section 2 - Study Population Characteristics

2.5 Recruitment and Retention Plan

Describe the following: 1) the planned recruitment methods including use of contact lists, databases or other pre-screening resources, advertisements, outreach, media / social media and referral networks or groups; 2) if there are known participant or study-related barriers to accrual or participation (based on literature or prior experience), please list these barriers and describe plans to address them to optimize success; 3) contingency plans for participant accrual if enrollment significantly lags behind accrual benchmarks; 4) participant retention and adherence strategies; 5) possible competition from other trials for study participants; 6) safeguards for vulnerable populations as appropriate (e.g., children, pregnant women); and 7) strategies for outreach to minorities and women.

2.7 Study Timeline

A milestone plan must describe the key milestones that need to be met throughout the lifecycle of the project to ensure its success; the processes that will be used to reach the milestones; and a timetable identifying when each of these key milestones will be met. All applicants must use the following definition of a milestone in their application: a scheduled event in the project timeline that signifies the completion of a major project stage or activity. Milestones must be relevant, achievable, and measurable. The research plan should include anticipated challenges to meeting milestones and propose potential mitigation or corrective actions strategies. Milestones should address overall recruitment and retention goals. The Terms and Conditions for an award under this FOA will include a milestone plan that is mutually agreed upon by the investigators and NIH.

Milestones of particular interest that should be described in the application may include, but are not limited to, the following:

• Complete finalized clinical protocol approved by NIH and/or Protocol Review Committee/DSMB as appropriate
• Final Informed Consent Form(s) and, if applicable, assent form(s)
• Agreements in place for clinician/provider participation and/or product supply (if applicable)
• Comprehensive laboratory plan (as applicable)
• Pharmacy/Laboratories Identification (as applicable)
• Contracts/Third Party Agreements (if applicable)
• Training plan for clinical site
• Final Data and Safety Monitoring Plan
• Site Performance Plan
• Data Completeness and Quality Monitoring Reporting Plan
• Completion of regulatory approvals
• IRB approval for clinical site(s)
• Collection of data related to primary and secondary endpoints and database lock
• Submission of primary outcome(s) manuscript to peer-reviewed scientific journal
• Submission of study results to ClinicalTrials.gov within 12 months of the primary completion date
• Data sharing plan for study data and biospecimens (if applicable)

During the award phase, achievement of each milestone will need to be communicated to the NIH Program Officer listed on the Notice of Award. Award continuation, even during the period recommended for support, is conditional upon satisfactory progress. If, at any time, recruitment falls significantly below projections, or core milestones mutually agreed upon by the PD/PI and the NIH, are not met, the NIH may consider ending support and negotiating an orderly phase-out of the award. The NIH retains, as an option, periodic external peer review of progress. NIH staff will closely monitor progress at all trial stages including milestones, accrual, and safety.

Please note: To transition from the R61 phase to the R33 phase, grantees will submit a transition request 3 months prior to the proposed transition date. Successful achievement of milestones must be documented prior to submission of the transition package.

Section 3 - Protection and Monitoring Plans

3.3 Data and Safety Monitoring Plan

All applications are expected to include a detailed data and safety monitoring plan. Applicants should refer to NIH’s policy on data and safety monitoring (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html).

For awards administered by NCCIH projects will be required to have an independent monitoring for research involving human subjects. Applicants should refer to the NCCIH Guidelines for Data and Safety Monitoring (http://nccih.nih.gov/grants/policies/data-safety-monitoring).

For projects proposing a clinical trial:

5.1 Other Clinical Trial-Related Attachments:

Clinical Trial Experience.

Applicants must provide a detailed table listing the characteristics of trials that demonstrate experience in trial conduct and/or coordination in the last 5 years. The table must be provided as an attachment called "Clinical Trial Experience.pdf", appended with 1, 2, 3, etc. as needed, and must not exceed 3 pages. Applications that do not include this attachment or exceed the page limit will not be peer reviewed.

The table columns should include:

Column A: clinical trial title

Column B: applicant's role in the trial

Column C: a brief description of the trial design

Column D: planned enrollment

Column E: actual enrollment

Column F: number of sites

Column G: whether the trial(s) were completed on schedule or not

Column H: publication reference(s)

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).

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

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

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.

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 components of participating organizations, 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.

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.

In addition, for applications involving clinical trials:

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

For this particular announcement, note the following:

The R61/R33 phased innovation grant supports highly innovative studies as well as a rapid translation of such insights into clinically relevant optimization strategies. While highly innovative work often inherently carries a substantial scientific risk (i.e., the original hypothesis may not be proven), this risk can be substantially mitigated by properly designed milestones that would help determine whether at the end of the R61 phase the study is ready to move forward to the R33 phase. A well-planned R33 phase is only meaningful if the R61 phase is both innovative and well-designed. An R61/R33 grant application need not have preliminary data, extensive background material or preliminary information; however, they should be included if available. Appropriate justification for the proposed work can be provided through literature citations, data from other sources, or, when available, from investigator-generated data. Accordingly, reviewers will emphasize the level of innovation, the potential to significantly optimize the proposed intervention, and the rigor of the proposed experimental designs. Reviewers will assign a single impact score for the entire application, which includes the R61 phase, the proposed R61-to-R33 transition milestones, and the R33 phase.

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

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

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

In addition, for applications involving clinical trials

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

Specific to this FOA:

How well does the project assess the impact of a behavioral/social intervention as an adjunct for MAT for OUD? If the aims are achieved, how will the behavioral/social intervention as an adjunct to MAT for OUD be generalizable beyond the environments in which the approach is being tested? If the primary outcomes of the proposed study are achieved, how critical will the information be to address the evidence gap and advancing knowledge of theory and practice? How would the results of the proposed study have a significant influence on the OUD crisis? Is there sufficient demonstration for the presence of clinical equipoise?

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

In addition, for applications involving clinical trials

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

Specific to this FOA:

How does the involvement of the relevant stakeholders enhance the feasibility, scientific impact, or relevance of the project? How strong is the application in demonstrating that the PDs/PIs and Key Personnel have the experience and capability to conduct the proposed study and meet milestones and timelines? How well defined are the investigators roles and responsibilities? What evidence is provided to ensure that the clinical facilities will employ the appropriate personnel to recruit subjects and implement the study protocol? How well does the application provide evidence of necessary experience and expertise of the investigators with the psychosocial intervention, the study population, and the research methods to be employed? For applications proposing a clinical trial, what evidence is provided to ensure that the investigators' clinical facilities will employ the appropriate personnel to recruit subjects and design/implement the clinical protocol? Does the investigative team have a track record of publishing the results of previously completed research?

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

In addition, for applications involving clinical trials

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

Specific to this FOA:

How will the proposed research change clinical practice or practice guidelines? Does the proposed research have the potential to advance the field even if the proposed study design, methods, and intervention are not innovative?

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?

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?

Specific to this FOA:

Is the study designed to generate causal inferences on the effects of behavioral/social approaches as an adjunct to MAT? Have investigators proposed methods to mitigate bias, error, and confounding? How strong is the evidence for equipoise? How well are the outcome measures, dose/duration of intervention and follow up, appropriateness of inclusion/exclusion criteria, and sample size justified and explained? How well does the Recruitment and Retention plan provide evidence that the accrual goals can be reached within the application? How appropriate is the plan to monitor accrual? Are there plans for adverse events to be appropriately captured and monitored? For the R61 phase will the proposed adaptions and tailoring provide the formative work to allow for a successful R33 phase? For the R33 phase will the chosen study design be appropriate for the stated goals of the project?

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

In addition, for applications involving clinical trials

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

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

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

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

Specific to this FOA:

Does the application document the availability of the requisite eligible subject pool in proposed recruitment site(s)? Is there documentation of the commitment of any subcontractors and consultants, as well as service agreements for personnel and facilities?

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

Study Timeline

Specific to applications involving clinical trials

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

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

R33 to R61 Transition Milestones

Do the milestones define clear assessment(s) that will justify the transition to the R33 phase? Are the proposed milestones relevant, achievable, and measurable? Does the research plan include anticipated challenges to meeting milestones and propose potential mitigation or corrective actions strategies? Do milestones address overall recruitment and retention goals?

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

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

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

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

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

Not Applicable

Not Applicable.

Not Applicable.

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

Not Applicable.

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

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

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

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

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

As part of the scientific peer review, all applications:

• 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.
• Will receive a written critique.

Appeals of initial peer review will not be accepted for applications submitted in response to this FOA.

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Board. The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.

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

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

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the 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 of all trials whether required under the law or not. For more information, see http://grants.nih.gov/ClinicalTrials_fdaaa/

Institutional Review Board or Independent Ethics Committee Approval: Grantee institutions must ensure that the application as well as 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).

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 law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. 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. HHS provides general 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/index.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-individuals/section-1557/index.html; and https://www.hhs.gov/civil-rights/for-providers/laws-regulations-guidance/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see https://www.hhs.gov/civil-rights/for-individuals/disability/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. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. 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 http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

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.

Cooperative Agreement Terms and Conditions of Award

Not Applicable.

When multiple years are involved, awardees will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement
A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

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.

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: [email protected] (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: [email protected]

Dave Clark, Dr.P.H.
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-827-1916
Email: [email protected]

Sarah Duffy, Ph.D.
National Institute on Drug Abuse (NIDA)
Telephone: 301-451-4998
Email: [email protected]

Brett Hagman, Ph.D.
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Telephone: 301-443-0638
Email: [email protected]

Meryl Sufian, Ph.D.
National Institute on Minority Health and Health Disparities (NIMHD)
Telephone: 301-594-8758
Email: [email protected]

Lisa Onken, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-496-3136
Email: [email protected]

Michael Freed, Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 301-443-3747
Email: [email protected]

Karen Lee, Ph.D.
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-827-3973
Email: [email protected]

Martina Schmidt, Ph.D.
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-594-3456
Email: [email protected]

Shelley Carow
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-594-3788
Email: [email protected]

Pamela Fleming
National Institute on Drug Abuse (NIDA)
Telephone: 301-480-1159
Email: [email protected]

Judy Fox
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Telephone: 301-443-4704
Email: [email protected]

Priscilla Grant, J.D.
National Institute on Minority Health and Health Disparities (NIMHD)
Telephone: 301-594-8412
Email: [email protected]

Nia Pree
National Institute on Aging (NIA)
Telephone: 301-827-6374
Email: [email protected]

Tamara Kees
National Institute of Mental Health (NIMH)
Telephone: 301-443-8811
Email: [email protected]

Bryan Clark, M.B.A..
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-435-6975
Email: [email protected]

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.