Required Application Instructions

It is critical that applicants follow the 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

Areas supported by this Funding Opportunity Announcement (FOA) include research to generate and conduct preliminary tests of targeted addiction treatment to address multiple substances, which may include alcohol, tobacco and drug dependence. Treatment targets, including behavioral, neurobiological, social, psychological and cognitive/ affective are essential to assessment and treatment of substance use disorders (SUDs). In line with an experimental therapeutics approach, targets are the processes by which substance use disorders are maintained, and the primary focus of the treatment that is developed, refined and/or adapted. Target engagement and validation occur when treatment exacts change on the specified target and when target engagement leads to and/or correlates with symptom reduction outcomes, respectively. Because these target domains are important in terms of assessment and treatment of addiction, and the fact that they have been shown to be malleable in response to treatment, this FOA will encourage studies to capitalize on the opportunities to develop novel treatments with coordinated referents across target and measurement domains. Treatments that incorporate target domains with pharmacological and/or behavioral interventions may help to improve treatment efficacy, retention, relapse prevention and long-term outcome. Given the importance of target domains in terms of setting the stage for treatment development and evaluation, data replication is paramount.

The purpose of this FOA is to provide support for applications that focus on data replication and the scalability of novel, targeted addiction treatments. Consistent with an experimental therapeutics approach, studies that would fall under the R33 (Phase II) would include studies with theory-derived targets (based on putative mechanisms of multiple substances) and clearly defined hypotheses about how the proposed treatment directed at changing the target relates to clinical outcomes. In addition, studies that include preliminary efficacy with respect to target engagement and validation (i.e., data to establish the relation between target and symptom reduction and functional outcomes) are essential to the Phase II arm (R33). Studies of novel treatments include, but are not limited to behavioral, pharmacological, biologics-based, cognitive, device-based, interpersonal, physiological, or combined approaches. This FOA provides support for replication studies of addiction treatment across 2 or more settings. Specifically, this phase will focus on clinical trials and clinical research that apply the target in a treatment setting (testing, refinement, and/or adaptation) to evaluate the efficacy and replicability of larger trials. Ultimately, the goal of this FOA is to replicate findings of mechanisms and processes underlying treatments or replication of strategies into novel intervention approaches that can be efficiently tested and replicated for their promise to address substance use disorder outcomes. Furthermore, these studies build on data that have been demonstrated with sufficient signal of target engagement from an analogous R21 study to justify the proposed R33 trials.

This FOA is part of an NIH initiative known as Collaborative Research on Addiction at NIH (CRAN; http://addictionresearch.nih.gov/ ). The mission of the CRAN is to provide a strong collaborative framework to enable the National Institute on Drug Abuse (NIDA), the National Institute on Alcohol Abuse and Alcoholism (NIAAA), and the National Cancer Institute (NCI) to integrate resources and expertise to advance addiction research and public health outcomes.

High rates of co-occurring substance use disorders contribute to excess morbidity and mortality, and also are associated with poorer long-term clinical outcomes. Although various combinations of behavioral and pharmacological treatments have been shown to be effective, relapse rates among individuals with substance use disorders remain high. Several factors have been implicated that largely account for these high rates. One in particular is the idea that many existing treatments often fail to capitalize on important target domains that have been linked to substance use disorder outcomes including behavioral, neurobiological, social, psychological and cognitive/ affective. These target domains and their underlying neurocircuitry play a critical role in the initiation and onset of substance use disorders (including course of treatment, treatment drop-out, relapse, and clinical outcomes), thereby making these target candidates an essential part of assessment and treatment of substance use disorders.

As conceptualized by a mechanism-focused, experimental therapeutics model, targets are the processes by which substance use disorders are maintained, and the primary focus of the treatment that is developed, refined and/or adapted. Target engagement is essential when evaluating the extent to which the treatment under study exacts change on the specified target. In order to ensure accuracy, it is equally important to validate that the target actually leads to and/or correlates with symptom reduction outcomes. Because these target domains are important in terms of assessment and treatment of addiction, and the fact that they have been shown to be malleable in response to treatment, opportunities exist to develop novel treatments with coordinated referents across target and measurement domains. Treatments that incorporate target domains with pharmacological and/or behavioral treatments may help to improve treatment efficacy, retention, relapse prevention and long-term outcome. An explicit focus on targets also may help to better evaluate and measure changes that correspond to clinically meaningful reductions in substance use or abuse. For example, perhaps improvements in cognitive or sensory deficits may result in decreases in drug use behaviors; changes in risk-taking propensity or greater task persistence also may result in reductions in drug use.

Greater treatment specificity among individuals with substance use disorders is essential in order to move beyond main effects on abstinence rates and better integrate and improve treatment efficiency treatment response-rate results. Therefore, the overarching goal of the R33 is to capitalize on preliminary data that has demonstrated target engagement (i.e., the degree to which target engagement produces the desired behavior change; leads to or correlates with symptom reduction and functional outcomes). Target engagement will be further explored in a treatment context across a minimum of 2 settings to further establish large-scale testing of efficacy and data replicability of treatments that improve multiple substance use disorder outcomes. Specifically, this R33 FOA requires the early, efficient, and objective testing of a treatment proposed mechanism of action to better define which treatment engages the target and thereby the treatment should be further tested, adapted and/or refined to establish data replication.

This FOA provides support for applications designed to (a) scale and replicate novel treatments and refine existing treatments and (b) conduct tests of novel and improved behavioral, pharmacological, and combined treatments for individuals with substance use disorders (multiple substances including alcohol, tobacco and drug dependence) by examining the mechanisms of addiction as putative treatment targets. Specifically, this FOA facilitates projects that employ an experimental therapeutic approach to treatment development with an emphasis on data replicability. As an example, the Stage model of treatment development provides an overarching framework to guide for R33 research (additional background on the "Stages" of behavioral treatment development are located in this FOA: https://grants.nih.gov/grants/guide/pa-files/PA-16-072.html). This FOA facilitates applications that are analogous to Stage II and III, treatment research to test efficacy, conduct clinical trials, examine mechanisms of behavior change, optimize combinations, and/or sequencing of behavioral, combined, sequential, or integrated behavioral and pharmacological treatments.

This approach requires the identification of a theory-derived target based on putative mechanisms of addiction among individuals with multiple substance use disorders, and clear hypotheses about how a treatment directed at changing the target can lead to clinical benefits. Consistent with an experiment therapeutics model, target refers to a disorder-maintaining process, which the intervention seeks to modify; target engagement occurs when an intervention in fact modifies this process; target validation occurs when target engagement leads to (or at least correlates with) symptom reduction outcomes; and mechanism of action (how the intervention works) encompasses both target engagement and target validation. Under this FOA, pilot trials should be designed so that results, whether positive or negative, will provide compelling information used to support decisions about further development and large-scale testing of the treatment.

This FOA seeks to stimulate research on the improved efficacy of substance use disorder treatment with an emphasis on data replicability. This FOA provides up to 3 years of support for Phase II (R33) to address data replication. Specifically, Phase II will conduct replication studies of substance use disorder treatment across a minimum of 2 treatment settings. This latter phase will facilitate applications that focus on multisite clinical trials.

This FOA encourages multisite clinical trials that are consistent with an experimental therapeutic approach. These applications will conduct testing, refinement and adaptation of novel, targeted treatments for substance use disorders across a minimum of 2 treatment settings.

Activities that are appropriate will depend on the type of treatment under study and its stage of development. Generally, these activities include: 1) operational definition and objective measures of the target; 2) evidence that the operational measures of the target can be reliably and validly manipulated; 3) demonstration of adequate target engagement, including established dose selection; 4) feasibility data to indicate that an adequate dose of the intervention (defined by target engagement) can be applied with adequate safety and tolerability; 5) protocol testing along with initial fidelity scales; and 6) adequate recruitment plans. For pharmacological treatments, unless preliminary data are available, studies must include determining the optimal dose for a subsequent trial by assessing dose-response with respect to a functional pharmacodynamic readout of target engagement.

The proposed clinical trial should demonstrate target engagement and test the link between the degree of target engagement and mechanism-based functional outcomes in a patient population. Studies supported by this FOA should be powered as strong tests of clinical efficacy, and should test a hypothesis about the treatment’s mechanism of action and inform whether there is consistency across the settings that warrants data reproducibility.

Successful applications will propose a theoretically-justified model and empirical support for the mechanism involved in triggering or maintaining the disorder, and a scientific rationale for the proposed treatment target approach. This FOA requires preliminary data for the proposed treatment that includes prior demonstration of target engagement. For example, rigorous tests of a target with objective, quantifiable, reproducible measures of target engagement (e.g., behavioral and/or biological levels) are applicable demonstrations of target engagement, including measures of structural (e.g., PET receptor occupancy) as well as functional (e.g., performance on a behavioral task, fMRI circuit activation) target engagement. Furthermore, they can include laboratory tasks that have been previously validated as reflecting underlying behavioral, psychological or neural mechanisms (e.g., go-no-go tasks to measure impulse control, reaction-time to the dot-probe task to measure cognitive attention bias, temporal discount rates to measure self-regulation). Measures of target engagement should be scientifically justified and be as objective and direct as is feasible. Self-report measures can add useful information in a multi-method/multi-measure design that is set to demonstrate construct and convergent validity.

This FOA provides support for treatment studies to evaluate the ability of the treatment to impact the hypothesized target and to assess the efficacy of the substance abuse treatments across sites to evaluate reproducibility.

Preliminary Requirements

This FOA supports testing of treatments for which the elements of proof-of-principle have already been demonstrated with sufficient signal of target engagement to justify the proposed treatment studies across sites.

Applications are expected to replicate and extend the initial target engagement findings from research that has been conducted analogous to that done in an R21 phase or other funded study, and to test the association between target engagement and functional or clinical outcome. Therefore, research activities under this FOA include further testing of target engagement by testing whether the intervention could cause the hypothesized changes in the target, and whether these changes are associated with subsequent substance use disorder and functional outcomes.

Examples of R33 Research

Targeted treatment research to improve substance use disorder outcomes, examples of areas of interest include, but are not limited to:

• Research aimed at testing behavioral targets (e.g., cognitive or sensory deficits, working memory, delay discounting, and/or task persistence) within treatments designed to modify these targets
• Novel stand-alone treatment to address substance use disorders aimed at putative targets
• Research to boost the efficacy to existing interventions to address substance use disorders
• Research to promote adherence to existing efficacious interventions
• Research conducting clinical trials on treatments that have been shown to engage specific neurobiological targets (i.e., receptor deficits, dopamine depletion, etc.) that seek to further demonstrate target engagement and link target engagement with substance use disorders and other functional outcomes
• Research conducting clinical trials of technology-based interventions that have been shown to engage specific behavioral and/or neurobiological targets, and that seek to further demonstrate target engagement and link target engagement with substance use disorders and other functional outcomes

Notes on Priorities

• Applicants are strongly encouraged to propose projects related to multiple substances, which may include polysubstance use or abuse. Consistent with the overall goals of the CRAN initiative, such projects will receive programmatic priority over projects focused on a single substance.
• Applications lacking a focus on an experimental therapeutic approach will not be considered a priority for funding.
• While the testing of targeted treatments may be done in randomized clinical trials, other methodologies may be used as appropriate (e.g., adaptive designs, multiphase optimization strategies).
• Studies comparing a novel intervention to other treatment or control conditions in the absence of an experimental approach to target identification, validation, and engagement will not be considered a priority.
• Studies that do not identify a treatment target; studies that do not propose a compelling rationale for a treatment target will not be considered a priority.

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 in response to 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:

o Hispanic-serving Institutions

o Historically Black Colleges and Universities (HBCUs)

o Tribally Controlled Colleges and Universities (TCCUs)

o Alaska Native and Native Hawaiian Serving Institutions

o 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)

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH 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) (formerly CCR) 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 and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. 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).

Applicants must obtain the SF424 (R&R) application package associated with this funding opportunity using the Apply for Grant Electronically button in this FOA or following the directions provided at Grants.gov.

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, including Supplemental Grant Application Instructions 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.

For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

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/NIH/DHHS
6001 Executive Boulevard, Suite 4243, MSC 9550
Bethesda, MD 20892-9550

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. The R33 phase should focus on replication studies of addiction treatment across 2 or more settings. Specifically, clinical trials should apply the target in a treatment setting (development, refinement, and/or adaptation) to evaluate the feasibility of conducting a larger trial.

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:

Research Strategy: Applicants are expected to describe how the results of prior research (R21 or similar-funded research) will inform a future efficacy study.

Applicants should provide a compelling scientific rationale for any measures proposed to assess the link between the hypothesized mechanism/target and clinical outcomes that are guided by an experimental therapeutics framework.

Applicants should delineate how the intervention approach is grounded in empirical evidence of disorder, mechanism of treatment effect, or mediators and moderators of treatment response. For studies of pharmacological interventions, a clear description should be included of the approach for determining pharmacological dose\response relationships and target engagement of the drug candidate.

Applicants should justify the need for the application. Research used to justify the R33 should be based on clear findings with detailed parameters having been met.

Applicants proposing adaptation of interventions with demonstrated efficacy should describe a compelling rationale supported by empirical evidence, and a hypothesized target that will be tested within an experimental framework.

The research design should allow for a demonstration of target engagement and change of the target in the hypothesized direction. In addition, applicants should propose concrete indicators of feasibility across sites and data to set the stage for larger clinical trials of efficacy.

Given the emphasis on data replicability across multiple sites, completeness and accuracy in terms of protocols, specific goals and milestones are critical. Milestones representing clearly defined aims should be feasible, well developed and quantifiable with regard to the specific aims. A feasible timeline also should be proposed. Feasible plans for sample size and timely recruitment should be delineated. As appropriate, a clear strategy for tracking recruitment and facilitating retention should be proposed.

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: Do not use the Appendix to circumvent page limits. 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 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 a delayed onset study record.

Study Record: PHS Human Subjects and Clinical Trials Information: All instructions in the SF424 (R&R) Application Guide must be followed.

Delayed Onset Study: All instructions in the SF424 (R&R) Application Guide must be followed.

(R&R) Application Guide.

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

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

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 Applying Electronically. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues. 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, NIH. Applications that are incomplete or non-compliant will not be reviewed.

Applicants requesting $500,000 or more in direct costs in any year (excluding consortium F&A) must contact a Scientific/ Research Contact at least 6 weeks before submitting the application and follow the Policy on the Acceptance for Review of Unsolicited Applications that Request $500,000 or More in Direct Costs as described in the SF424 (R&R) Application Guide.

Applicants are required to follow our Post Submission Application Materials policy.

Important Update: See NOT-OD-18-228 for updated review language for due dates on or after January 25, 2019.

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

For this particular announcement, note the following:

The R33 application should focus on replication studies of addiction treatment across 2 or more settings. Specifically, clinical trials that apply the target in a treatment setting (development, refinement, and/or adaptation) to evaluate the feasibility of conducting a larger trial.

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).

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

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 there a strong scientific premise for the project? 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 proposing 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 the trial needed to advance scientific understanding?

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 proposing 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?

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 proposing 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?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the 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?

Is the readiness for the application justified? Does the application include valid measures of target identification and engagement and initial evidence that the intervention engages the target? Is the study proposed in the application designed to measure the prospective association between target engagement and clinical outcomes? Are the proposed milestones clearly defined? Are these milestones feasible, well-developed and quantifiable with regard to the specific aims? Is the timeline feasible? Are the plans for sample size and timely recruitment of subjects clear and feasible? Is there a clear strategy for tracking recruitment and facilitating retention?

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 children, justified in terms of the scientific goals and research strategy proposed?

In addition, for applications proposing clinical trials: Does the application adequately address the following, if applicable:

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?

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?

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 proposing 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 proposing 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)?

For research that involves human subjects but does not involve one of the six 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 six 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 children 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.

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

For Renewals, the committee will consider the progress made in the last funding period.

For Revisions, the committee will consider the appropriateness of the proposed expansion of the scope of the project. If the Revision application relates to a specific line of investigation presented in the original application that was not recommended for approval by the committee, then the committee will consider whether the responses to comments from the previous scientific review group are adequate and whether substantial changes are clearly evident.

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.

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

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 the Center of 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:

• 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.

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.

Additionally, ICs may specify any special reporting requirements for the proposed clinical trial to be included under IC-specific terms and conditions in the NoA. For example: If the proposed clinical trial has elevated risks, ICs may require closer programmatic monitoring and it may be necessary to require the awardee to provide more frequent information and data as a term of the award (e.g., to clarify issues, address and evaluate concerns, provide documentation). All additional communications and information related to programmatic monitoring must be documented and incorporated into the official project file. 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.nig.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 http://www.hhs.gov/ocr/civilrights/understanding/section1557/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 http://www.hhs.gov/ocr/civilrights/understanding/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.

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 progress report, 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.

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 registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Finding Help Online: https://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact CenterTelephone: 800-518-4726

Email: support@grants.gov

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

Will M. Aklin, Ph.D.
National Institute on Drug Abuse (NIDA)
Telephone: 301-443-3207
Email: aklinwm@mail.nih.gov

Glen Morgan, Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276-6787
Email: glen.morgan@nih.gov

Brett Hagman, Ph.D.
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Telephone: 301-443-0638
Email: brett.hagman@mail.nih.gov

Weijia Ni, Ph.D.
Center for Scientific Review (CSR)
Telephone: 301.594.3292
Email: niw@csr.nih.gov

Ericka Wells
National Institute on Drug Abuse (NIDA)
Telephone: 410-254-1853
Email: wellse2@nida.nih.gov

Jacquelyn Boudjeda
National Cancer Institute (NCI)
Telephone: 240-276-6312
Email: Boudjedaj@mail.nih.gov

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

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.