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

Purpose

Genetic and genomic studies have identified genes and gene variants that may impact the fundamental biological mechanisms underpinning substance use disorders (SUDs). Discovery of these genes/variants, while extremely valuable, is only the first step in understanding the molecular processes that influence SUDs. This Funding Opportunity Announcement (FOA) encourages basic functional genetic and genomic research in two areas: 1. functional validation to determine which candidate genes/variants/epigenetic/non-coding RNA features have an authentic role in SUDs, and 2. detailed elucidation of the molecular pathways and processes modulated by candidate genes/variants, particularly for those genes with an unanticipated role in SUDs.

Background

Genes. SUDs and dependence on addictive substances (including opioids, prescription drugs, nicotine, methamphetamine, cannabis, stimulants, and inhalants) are a major public health and economic problem. Candidate genes/variants that play roles in SUDs have been identified using human or animal genome-wide association scans, QTL characterization, gene expression profiling, forward or reverse genetic screens, proteomics, or through epigenomic analyses. Genes and variants identified by these methods are priority targets for functional validation. Other candidate genes/variants include those correlated with co-occurring psychiatric disorders, SUD-relevant behaviors, or genes relevant to other areas of NIDA’s mission, including pain and HIV/AIDS susceptibility and progression.

Functional Validation. The most desirable functional validation is the demonstration of an epigenetic or genetic variant’s effect on a human phenotype relevant to SUD. However some human functional validation studies may not be feasible or ethical, necessitating the use of in vivo animal models or in vitro strategies. Effects of copy number variation, modified chromatin states, methylation patterns, higher order chromatin structure, transcriptional regulation as well as how these changes are influenced by genetic variation are of interest. An epigenetic or genetic variant could manifest itself phenotypically at the level of a molecular pathway, cell, circuit, organism, or social interaction, leading to phenotypic differences in protein function, cell morphology, neural connectivity, behavioral responses to an addictive substance, or behavioral responses to social cues. Validation studies are encouraged at any of these levels to identify phenotypic differences relevant to addictive processes and further elucidate the driving molecular pathways that converge to elicit biobehavioral changes.

Resources. There are numerous public and private resources available to facilitate functional validation of genes/variants involved in addiction. NIDA promotes the mining of databases to obtain insight into the molecular mechanisms of epigenetic or genetic variant function in SUDs. Some of these databases include information on model organism phenotypes (e.g. Mouse Genome Informatics, Wormbase, Flybase, ZFIN), physically interacting proteins, epigenomic/transcriptomic data (e.g. Roadmap Epigenomics Program, ENCODE, IHEC), human eQTLs/transcriptomic data (GTEx) to obtain insight into the molecular mechanisms of epigenetic or genetic variant function in addictive processes. Publicly available mutants in yeast, C. elegans, Drosophila, zebrafish, mouse, and other models can be used for functional tests. For example, to test hypotheses about gene function and SUDs, the Knock Out Mouse Project (KOMP) provides ES cells that can be used to generate knockout animals. Recent improvements in gene editing can also be exploited to generate transgenic animals in both widely used and emerging models. Reagents for RNA knockdown of genes are available for functional validation studies. Researchers may also exploit iPS cells, human tissue banks, and post-mortem tissue collections for validation studies. For many available resources see Neuroscience Information Framework (http://www.neuinfo.org/).

Potential Research Areas and Approaches

Applicants proposing to functionally validate genetic findings or to elucidate functional mechanisms for putative genes relevant to SUDs are encouraged to apply to this FOA. The R21 activity code is intended to encourage new exploratory and developmental research projects. These studies may involve considerable risk but may lead to a breakthrough in a particular area, or to the development of novel techniques, agents, methodologies, models, or applications that could have a major impact on a field. Applicants proposing high risk/high payoff exploratory/developmental research projects with limited preliminary data are encouraged to submit an R21 grant application through this FOA, while applicants proposing discrete projects with substantial preliminary data are encouraged to submit an R01 grant application using the companion FOA. Applicants proposing to discover new genes or gene variants involved in SUDs may also apply using the related NIDA PA-17-120 "Discovering Novel Targets: The Molecular Genetics of Drug Addiction and Related Co-Morbidities (R01). Applications to this FOA can vary greatly in depth and breadth of analysis. They may investigate a single high priority epigenetic or genetic variant in detail (e.g. using gene editing approaches) or test several hundred genes/variants rapidly (e.g. using high throughput RNA knockdown).

NIDA seeks to understand addiction to substances such as prescription drugs, nicotine, methamphetamine, cocaine, cannabis, opioids, and inhalants. Applicants should therefore focus on one or more NIDA-relevant substances. Applicants proposing to investigate alcohol in concert with one or more NIDA-relevant substances may also submit their application to this FOA. However, this FOA is not intended for applications investigating ONLY the effects of alcohol.

The following list highlights some areas of functional genetic/genomic research that would be of interest:

Human Studies. Functional validation studies could use human DNA samples from phenotypically well-characterized individuals to correlate a gene variant with a particular phenotype and/or endophenotype. Similarly, post-mortem tissue could be used for allele-specific gene expression, epigenomic mapping, or other studies. Researchers performing assays that measure epigenomic or somatic genomic features are encouraged to focus on tissues directly relevant to the disease being investigated. Induced pluripotent stem cells (iPS cells) and neurons, other cell types, or organoids derived from these cells may be useful for investigating the function of a genetic variant.

Comparison of Wild type and Gene Variant Functions. The molecular alteration associated with a gene variant frequently does not reveal whether the function of a particular gene is increased, decreased, or leads to unexpected functional consequences. Yet this information is critical if one wishes to exploit a gene variant to develop a therapeutic approach. Approaches using in vivo transgenes, in vitro biochemical assays, or other validation methods that can address these issues will help to identify the most promising molecular targets for therapeutic interventions to treat addictions.

Addictive behavior. Approaches that can ascribe a functional role to an epigenetic and/or genetic variant with respect to a particular aspect of addictive behavior (e.g. drug reinforcement, tolerance, withdrawal, craving, reinstatement) are of great interest, as are strategies to identify epigenetic and/or genetic variant effects on behavioral responses to other drugs or addictive stimuli, stress, changes in social situations, food, other natural rewards, or other environmental stimuli. In general, applicants are advised to carefully consider their selection of a behavioral model of drug exposure or SUD and to justify why this behavioral model is the most compelling choice for the proposed aims of their application.

Genetic Models. Established genetic models (such as yeast, C. elegans, sea slug, Drosophila, zebrafish, mouse, rat, and primate) as well as emerging genetic models (e.g. marmoset) can be used to examine in vivo epigenetic and/or genetic variant function. Strategies could include exploitation of available genetic knockouts or other mutants, knock in of gene variants, or conditional reduction or overexpression of wild type and variant alleles. Since some model organism genomes (e.g. C. elegans and Drosophila) do not encode obvious opioid or cannabinoid receptors, functional validation studies involving these pathways would need to use genetic models such as zebrafish or mice. Cross-species validation of functional alleles is encouraged, as are studies investigating sex differences with respect to epigenetic and/or genetic variant function. Functional validation approaches that could lead to the development of in vivo models of addictive processes or could facilitate future screening for therapeutic agents are of great interest.

Genomic Manipulation. Depletion of candidate gene mRNAs in cells, tissues, brain regions, or whole organisms using RNA interference or related approaches can be used to discover or validate phenotypes. These phenotypes could range from the cellular (e.g. changes in morphology or function of synapses, dendritic spines, or neurons) to the organismal (e.g. changes in behavioral responses to addictive substances). Similarly, applicants may wish to exploit locus-specific genome editing or epigenome manipulation strategies to address genetic or epigenetic function. Strategies to investigate the effects of genetic or epigenetic variants in specific cell types or during specific temporal windows using opto-epigenetic or chemo-epigenetic approaches are also encouraged.

Epigenetics and Epigenomics. Identification of cell type-specific epigenomic features associated with addictive processes as well as functional validation of epigenetic mechanisms of gene regulation in the context of neuroscience or addiction biology are encouraged as are studies aiming to discover or better characterize histone or DNA modifications important for neuronal signal transduction or regulation of gene expression. Exploitation of chromatin structure assays (e.g. Hi-C, ChIA-PET, ATAC-seq) or microscopy techniques to explore chromatin dynamics in response to addictive substances are also of interest. Given the complications of cellular heterogeneity, robust single cell approaches are also encouraged.

Somatic Genomic Variation and Regulatory Elements. Studies investigating somatic genomic variation and its regulation and function in the nervous system and in response to addictive substances (including the role of repetitive DNA, retrotransposons, and other sources of somatic genomic variation as well as their potential functional effects on gene expression, alternative splicing, or chromatin state) are encouraged. Studies exploiting artificial somatic genomic variation such as DNA barcoding to tag brain cells for cell censuses, connectivity studies, or functional characterization are also of interest. Studies to assign SUD-related function to variants in non-coding RNAs, microRNAs, gene regulatory elements, transposable elements, or other putative non-protein coding regions of the genome are appropriate.

Non-coding RNAs and RNA Modifications. Studies to identify and characterize non-coding regulatory RNAs relevant to neuroscience and addictive processes are encouraged. Applicants might wish to investigate the role of miRNA regulation in SUDs, especially the identification of miRNA targets and associated mechanistic pathways. Investigations into novel and poorly understood classes of regulatory non-coding RNAs such as circular RNAs (circRNAs), long non-coding RNAs (lncRNAs), or RNAs associated with chromatin are of great interest. Applications investigating the potential functional roles of RNA modifications in mRNAs or regulatory RNAs in the nervous system are also encouraged.

Systems-level Approaches. Bioinformatic resources can be mined to identify causal genes or gene variants or to generate testable hypotheses concerning the function of candidate genes and groups of genes. Some data types that could be used include: gene expression, epigenomic, transcription factor binding information, proteomic, metabolomic, interactome, functional genomic, in silico mapping data, connectome, or neuroanatomical expression. Studies could test to see if sets of candidate disease genes are co-expressed in a particular brain region or cell type, or function together in a signal transduction cascade.

Cellular or Circuit-level Approaches. Studies comparing epigenetic and/or genetic variant functional consequences at the cellular and circuit levels, especially with respect to drug challenge are encouraged. Such outcomes may include, but are not limited to, studies of differences in neurotransmission, intracellular trafficking of proteins or RNAs, neurophysiology, signal transduction, as well as synaptic and dendritic physiology or morphology.

Developmental and Transgenerational Studies. Investigations into the functional effects of genes/variants on organism development in the context of drug exposure and SUD pathways are also of great interest. Approaches investigating epigenetic and/or genetic variant roles in neuronal differentiation, brain patterning, circuit formation, plasticity of brain circuitry during adolescence, gene x environment, gene x development, or gene x environment x development functional effects are all appropriate. In addition, there are some indications that parental exposure to certain addictive substances may lead to transgenerational phenotypic effects. Studies exploring these effects, including whether or not they are inherited through epigenetic or non-epigenetic mechanisms, are encouraged.

Imaging Strategies. Studies to identify in vivo human or animal gene/variant/epigenetic effects on neuronal activity or brain functions relevant to addiction are appropriate. These may include specific behaviors associated with addictive processes that are influenced by neurocircuitry or neuroconnectivity that may be assessed by imaging techniques such as fMRI, DTI, MRS, or PET. Studies in live, behaving animals that examine brain function in response to addictive substances are encouraged, especially in animal models of adolescent drug exposure.

Brain Energetics. Studies investigating the functional interplay between molecular regulation of brain energy utilization and brain and/or behavioral changes resulting from chronic exposure to addictive substances are of interest.

Extracellular Vesicles and RNAs. Secreted extracellular vesicles (EVs) such as exosomes and microvesicles play an important role in many biological processes. EVs appear to play several interesting roles in the nervous system and may function in 1. neuronal-glial communication, 2. synaptic plasticity, and 3. immune surveillance. Potential studies could include: 1. the functional role of EVs and their cargoes in the nervous system, particularly with respect to neuroplastic processes and SUDs, 2. whether or not EVs in serum, cerebral spinal fluid, or other body fluids might be useful biomarkers for addictive substance exposure or SUD trajectory, and 3. whether or not EVs might have therapeutic utility for cell-specific treatment of SUDs. In addition, studies of extracellular RNAs complexed with proteins or other carriers are also of interest.

HIV/AIDS. Functional genetic and genomic studies relevant to HIV/AIDS infection and/or progression, including molecular regulation of HIV latency are encouraged.

Translational. The use of functionally validated gene variants, RNAs, or proteins for clinical applications or as validated biomarkers to predict phenotypes are of interest, as is the development of cell-type specific targeting approaches to deliver DNA, RNA, protein or other potentially therapeutic cargoes.

Special Considerations

National Advisory Council on Drug Abuse Recommended Guidelines for the Administration of Drugs to Human Subjects: The National Advisory Council on Drug Abuse (NACDA) recognizes the importance of research involving the administration of drugs with abuse potential, and dependence or addiction liability, to human subjects. Potential applicants are encouraged to obtain and review these recommendations of Council before submitting an application that will administer compounds to human subjects. The guidelines are available on NIDA's Web site at http://www.drugabuse.gov/funding/clinical-research/nacda-guidelines-administration-drugs-to-human-subjects.

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

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

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

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:

• 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)

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).

Buttons to access the online ASSIST system or to download application forms 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, 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.

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:

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 conducting clinical research, follow all instructions for completing PHS Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.

Form only available in FORMS-E application packages for use with due dates on or after January 25, 2018.

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.

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 are required to follow the instructions for post-submission materials, as described in the 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 R21 exploratory/developmental grant supports investigation of novel scientific ideas or new model systems, tools, or technologies that have the potential for significant impact on biomedical or biobehavioral research. An R21 grant application need not have extensive background material or preliminary information. Accordingly, reviewers will focus their evaluation on the conceptual framework, the level of innovation, and the potential to significantly advance our knowledge or understanding. Appropriate justification for the proposed work can be provided through literature citations, data from other sources, or, when available, from investigator-generated data. Preliminary data are not required for R21 applications; however, they may be included if available.

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 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?

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?

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?

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? 

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?

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?

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.

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.

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.

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 CSR, 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 to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications. Following initial peer review, recommended applications will receive a second level of review by the National Advisory Council on Drug Abuse. 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.

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.

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 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.

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 registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, 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)

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact Center Telephone: 800-518-4726
Email: [email protected]

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-710-0267

John Satterlee, Ph.D.
National Institute on Drug Abuse (NIDA)
Telephone: 301-435-1020
Email: [email protected]

Examine your eRA Commons account for review assignment and contact information (information appears two weeks after the submission due date).

Pamela Fleming
National Institute on Drug Abuse (NIDA)
Telephone: 301-480-1159
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.