Participating Organization(s)	National Institutes of Health (NIH)
Components of Participating Organizations	National Institute on Alcohol Abuse and Alcoholism (NIAAA) National Institute on Drug Abuse (NIDA)
Funding Opportunity Title	Mechanisms of Alcohol and Stimulant Co-Addiction (R21)
Activity Code	R21 Research Project Grant
Announcement Type	New
Related Notices	NOT-OD-16-004 - NIH & AHRQ Announce Upcoming Changes to Policies, Instructions and Forms for 2016 Grant Applications (November 18, 2015) NOT-OD-16-006 - Simplification of the Vertebrate Animals Section of NIH Grant Applications and Contract Proposals (November 18, 2015) NOT-OD-16-011 - Implementing Rigor and Transparency in NIH & AHRQ Research Grant Applications (November 18, 2015) June 4, 2014 - Notice NOT-14-074 supersedes instructions in Section III.3 regarding applications that are essentially the same.
Funding Opportunity Announcement (FOA) Number	PA-13-340
Companion Funding Opportunity	PA-13-339, R01 Research Project Grant
Number of Applications	See Section III. 3. Additional Information on Eligibility.
Catalog of Federal Domestic Assistance (CFDA) Number(s)	93.273, 93.279
Funding Opportunity Purpose	This FOA encourages R21 applications from institutions/organizations that propose to study the neurobiological and behavioral mechanisms that might explain how alcohol and stimulants interact at genetic, epigenetic, cellular, neurocircuitry and behavioral levels to promote co-addiction.

Posted Date	August 28, 2013
Open Date (Earliest Submission Date)	January 16, 2014
Letter of Intent Due Date(s)	Not Applicable
Application Due Date(s)	Standard dates apply, by 5:00 PM local time of applicant organization. Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.
AIDS Application Due Date(s)	Standard AIDS dates apply Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.
Scientific Merit Review	Standard dates apply
Advisory Council Review	Standard dates apply
Earliest Start Date	Standard dates apply
Expiration Date	January 8, 2017
Due Dates for E.O. 12372	Not Applicable

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

This Funding Opportunity Announcement (FOA) encourages grant applications to examine mechanisms underlying interactions between alcohol and stimulants. Co-occurring use of alcohol and stimulants is common. However, the behavioral and neurobiological reasons for polydrug use and emergence of concurrent dependence on alcohol and stimulants require further study. The purpose of this FOA is to promote research to study the neurobiological and behavioral mechanisms that might explain how alcohol and stimulants interact at genetic, epigenetic, cellular, neurocircuitry and behavioral levels to promote co-addiction.

By using the R21 activity code, this FOA seeks to foster the introduction of novel scientific ideas, model systems, tools, agents, targets, and technologies that have the potential to substantially advance biomedical research. Applications for R21 awards should describe projects distinct from those supported through the traditional R01 mechanism. For example, long-term projects, or projects designed to increase knowledge in a well-established area, will not be considered for R21 awards. Applications submitted under this mechanism should be exploratory and novel. These studies should break new ground or extend previous discoveries toward new directions or applications.

Background

Many people who drink alcohol also use other psychoactive drugs such as nicotine, cocaine, amphetamine, methamphetamine and caffeine. According to the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), one of the largest surveys of its kind, people who are dependent on alcohol are much more likely than the general population to use drugs, and people with drug dependence are much more likely to drink alcohol. Interestingly, polydrug use is most common in teens and young adults.

Given the common use of alcohol and stimulants in combination and a lack of known causal factors leading to this outcome, there is a need to better understand the mechanisms that underlie their co-use and co-addiction. This phenomenon could occur as a chance intersection where the use of one drug has no influence on the use of the other. However, some findings suggest that it may be the result of a number of interactive influences such as genetic, epigenetic, pharmacological, neuroadaptive, or behavioral factors. For example, specific genes may be predictive of both alcohol and stimulant use, these drug combinations may produce synergistic subjective drug effects, or the use of one drug may offset the undesired effects of the other. While there is some evidence for each of these hypotheses, the mechanisms underlying such interactions have not been thoroughly investigated.

Genetic and epigenetic mechanisms of alcohol and stimulant co-addiction

The heritability of alcohol and stimulant addiction has been convincingly demonstrated by family, twin and adoption studies over the last forty years. Heritability estimates for alcohol dependence range from 40 to 60%, while stimulant addiction including cocaine, amphetamine, methamphetamine and caffeine range from 40 to70%. Therefore, it is clear that genetic factors may play a substantial role in susceptibility to alcohol and stimulant addiction. However, whether there are common genetic factors that influence susceptibility to alcohol and stimulant addiction has not been thoroughly studied, even though alcohol and stimulant addiction frequently co-occur in the same individual. Candidate gene association studies have shown that genetic variation in a number of genes that are expressed in the brain is correlated with both alcohol and stimulant abuse/dependence. Likewise, family based studies have identified genes that may be common genes associated with alcohol and stimulant addiction. In addition to direct genetic factors, epigenetic factors could also underlie the common biological mechanisms of co-abuse of alcohol and stimulants. This FOA encourages applications that examine the common genetic factors that influence both alcohol and stimulant addiction. In addition, this FOA seeks applications that examine epigenetic factors that may have a common influence on alcohol and stimulant addiction.

Neurotransmitter and neuropeptide mechanisms underlying alcohol and stimulant co-addiction

Human and animal studies have shown that many addictive drugs affect common brain targets. Alcohol and stimulants exert their reinforcing effects through complex interactions with many neurotransmitters including dopamine, GABA, glutamate, serotonin and acetylcholine. This avails a range of receptor systems through which alcohol and other drugs may interact to enhance their ingestion.

Although common substrates may be involved in the reinforcing effects of many drugs, the possibility that other distinct actions of these drugs contribute to antagonistic effects must also be considered. For example, methylphenidate, at doses which do not affect locomotion, increased the locomotor stimulating effects of ethanol and decrease alcohol drinking. Because reinforcing effects were not directly measured in this study it is not possible to conclude whether reduced drinking after methylphenidate treatment reflected enhanced or decreased rewarding effects. Nonetheless, these results suggest a potentially complex interaction of common and/or distinct neurobiological mechanisms underlying the effects of methylphenidate and alcohol. A study in monkeys did not find additive or interactive effects of alcohol and cocaine, but instead suggested that when alcohol and cocaine are combined, alcohol decreased the reinforcing efficacy of cocaine, as indexed by rates of responding and elasticity of demand curves. This finding suggests that use of alcohol in combination with psychomotor stimulant drugs may not be due to an ability of alcohol to enhance the reinforcing effects of these drugs (or vice versa). Thus, when alcohol and other drugs are used in combination, it is important to examine both common and separate molecular mechanisms that could contribute to their co-use. Studies of other molecular targets (e.g., CART peptides, opioid and cannabinoid receptor system) and their functional roles in alcohol and stimulant co-use and addiction are also encouraged.

Role of neuroimmune factors in alcohol and stimulant co-addiction

Alcohol and stimulants have both neuronal and central immune modulatory signaling properties that can combine to induce reward and dependence behaviors that are associated with repeated exposure. For example, evidence from alcohol and cocaine literature provide a link to the possible role of Toll-like receptor 4 (TLR 4), an innate immune system molecule, in initiating the proinflammatory central immune signaling that may contribute to their abuse potential. Similarly, there is substantial evidence linking central immune signaling to methamphetamine and amphetamine behavioral responses including reward. For example, co-administration of amphetamine with minocycline (i.e., a tetracycline antibiotic that interacts with brain glutamate and dopamine neurotransmission) in humans revealed that glial attenuation blocked the reward, specifically the high and good effects experienced following amphetamine. Studies have also investigated the effects of pharmacological glial attenuators on methamphetamine behavioral responses. A recent study using ibudilast, an antiinflammatory drug which acts as a phosphodiesterase inhibitor, attenuated methamphetamine relapse in rats under prime- and stress-induced models. A Phase I safety interaction trial is currently underway to determine the possible clinical use of ibudilast as a novel treatment for methamphetamine dependence. These findings suggest that methamphetamine and amphetamine both contribute to alterations in proinflammatory central immune signaling which may interact with reward neurocircuitry in fashion that will drive reinforcement and promote further drug abuse. It remains to be determined, however, how neuroimmune factors regulate the neurotransmitter and neuropeptide systems involved in alcohol and stimulant co-abuse and how alcohol and stimulant co-use can influence neuroimmune factors and associated transductions pathways in targeted brain areas.

Role of conditioned and discriminative stimuli in alcohol and stimulant co-addiction

Situational cues associated with drugs can elicit feelings of craving and trigger relapse in people trying to maintain abstinence. Similarly, alcohol and stimulants produce well-defined interoceptive states that can prime further drug use such as when a priming dose of alcohol reinstates pressing a lever previously reinforced by alcohol. Ingesting two (or more) drugs in close temporal proximity raises the possibility that: (a) internal stimulus effects of one drug precipitates the ingestion of the second drug, and (b) the interoceptive states produced by each drug combine to form a compound stimulus that triggers further drug and stimulant use. These possibilities require further experimental attention. Additional studies suggest alcohol may alter stimulus effects of stimulants. For example, alcohol intoxication may increase attentional bias for cocaine cues in individuals who regularly use the drugs together since the interoceptive effects of alcohol have been repeatedly paired with the effects of cocaine. Therefore, the experience of these discriminative stimulus effects may increase attentional bias for cocaine cues through a classical conditioning process such that during abstinence from one drug, cues associated with ingesting the other could precipitate subjective craving and relapse. This possibility has received very little experimental attention, but may be important for designing future treatment plans. An additional treatment concern in cases of multiple drug addiction is that the stress of quitting one drug could trigger or escalate use of the other drug. Animal studies have shown when two behaviors are reinforced concurrently in the same environment (as is often the case with stimulant use and drinking), the discontinuation of one reinforcer (e.g., a stimulant) can trigger the resurgence of behaviors directed toward the other reinforcer (e.g., drinking). In light of the examples given above, this FOA encourages studies to examine the consequences of discontinuing or administering one drug (i.e., either alcohol or stimulant) on reinstating ingestion of the other.

Neuroadaptation of circuits associated with alcohol and stimulant co-addiction

Repeated alcohol or stimulant use lead to tolerance, dependence, and sensitization resulting from neuroadaptation that may be associated with the transition from controlled to uncontrolled drug and alcohol use. Alcohol, stimulants, and most drugs of abuse have profound effects on the mesolimbic reward circuit. Most notably, consumption is associated with increased extracellular dopamine in the nucleus accumbens. Significant efforts toward understanding substance use and abuse have focused on this pathway and it is clear that major changes occur in this circuit during the transition from drug use to drug abuse. However, ongoing work suggests that neuroadaptations occur in other important networks including the extended amygdala, which is associated with negative affect resulting from repeated withdrawal episodes, and cortical control circuits that are associated with craving and relapse. Within each of these circuits specific neurotransmitter systems are implicated generally (e.g. reward circuit and dopamine, extended amygdala and corticotropin-releasing hormone), but little is known about how these circuits function or adapt in the presence of co-use. As an example, the use of Disulfiram has been recently explored for the treatment of alcohol- and cocaine-dependence separately or in combination. Disulfiram was historically used to treat alcohol dependence and thought to be effective through its inhibition of aldehyde dehydrogenase. However, more recent work has demonstrated that it can reduce craving for both alcohol and cocaine through blockade of dopamine beta hydroxylase, increasing dopamine implicating the reward circuit in co-abuse and treatment. Studies are solicited to explore the circuits, neurotransmitter systems and neuroadaptations associated with the development, persistence, treatment and recurrence of alcohol and stimulant co-abuse.

Many factors can influence alcohol-stimulant interactions. For example, co-administration of alcohol and stimulants may increase their abuse liability via pharmacokinetic and/or pharmacodynamic properties, the production of new psychoactive metabolites, or through another mechanism(s) yet to be identified. There also may be a cross-tolerance between alcohol and the co-ingested substance. Moreover, genetic vulnerability and/or long-term alcohol use could perturb neural systems in ways that contribute to the dependence phenotype. Therefore, a multilevel analysis of genetic, neurocircuitry, and behavioral influences is needed to identify the range of shared and unique mechanisms involved in addiction to alcohol and stimulants. Such an in-depth approach will lead to more effective treatment and prevention strategies for alcohol and stimulant co-addiction.

Areas of research interest include but are not limited to:

• Identifying genetic and epigenetic factors that underlie the joint vulnerability to alcohol and stimulant addiction.
• Determining whether the reinforcement induced by the combination of alcohol and stimulants is additive or synergistic.
• Determining whether the combined use of alcohol and stimulants diminishes negative effects associated with either substance.
• Identifying the common or distinct molecular pathways, circuitry and neurotransmitter systems that mediate alcohol and stimulant co-use and addiction.
• Determination of the functional roles of glutamate, opioid, and cannabinoid receptor systems in concurrent alcohol and stimulant use and addiction.
• Examining the role of cross-tolerance as a common mechanisms underlying alcohol and stimulant (specifically, amphetamine, methamphetamine, and caffeine) co-addiction
• Examining the role of conditioned cues and their interactions in concurrent alcohol and stimulant use and addiction.
• Examination of discriminative stimuli for alcohol and stimulants and determining whether these stimuli interact to promote alcohol and stimulant use and relapse.
• Determining how neuroimmune factors regulate the neurotransmitter and neuropeptide systems involved in alcohol and stimulant co-addiction and how alcohol and stimulant co-use can influence neuroimmune factors or associated transductions pathways in targeted brain areas.
• Identifying neuroadaptations that occur in the presence of alcohol and stimulant co-use and addiction.

Funding Instrument	Grant: A support mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity.
Application Types Allowed	New Resubmission Revision The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.
Funds Available and Anticipated Number of Awards	The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications.
Award Budget	The combined budget for direct costs for the two year project period may not exceed $275,000. No more than $200,000 may be requested in any single year.
Award Project Period	The total project period may not exceed 2 years.

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 and should work with their organizational officials to either create a new account or to affiliate an existing account with the applicant organization’s eRA Commons account. 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.

NIH will not accept any application that is essentially the same as one already reviewed within the past thirty-seven months (as described in the NIH Grants Policy Statement), except for submission:

• To an RFA of an application that was submitted previously as an investigator-initiated application but not paid;
• Of an investigator-initiated application that was originally submitted to an RFA but not paid; or
• Of an application with a changed grant activity code.

Applicants must download 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, 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 forms package associated with this FOA includes all applicable components, required and optional. Please note that some components marked optional in the application package are required for submission of applications for this FOA. Follow all instructions in the SF424 (R&R) Application Guide to ensure you complete all appropriate optional components.

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, with the following additional instructions:

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) 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 Planned Enrollment Reports as described in the SF424 (R&R) Application Guide.

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

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.

Part I. Overview Information contains information about Key Dates. 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.

Organizations must submit electronic 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. If a Changed/Corrected application is submitted after the deadline, the application will be considered late.

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.

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 by the Center for Scientific Review, NIH. Applications that are incomplete will not be reviewed.

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-13-030.

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.

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.

Significance

Does the project address an important problem or a critical barrier to progress in the field? 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?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or 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?

Innovation

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

Approach

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

If the project involves clinical research, are the plans for 1) protection of human subjects from research risks, and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion of children, justified in terms of the scientific goals and research strategy proposed?

Environment

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

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.

Protections for Human Subjects

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.

Inclusion of Women, Minorities, and Children 

When the proposed project involves clinical research, the committee will evaluate the proposed plans for inclusion of minorities and members of both genders, as well as the inclusion of children. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Biohazards

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

Resubmissions

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.

Renewals

Not Applicable

Revisions

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.

Applications from Foreign Organizations

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.

Select Agent Research

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

Resource Sharing Plans

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

Budget and Period of Support

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

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

As part of the scientific peer review, all applications:

• 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. 

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 the DUNS, SAM Registration, and Transparency Act requirements as noted on the Award Conditions and Information for NIH Grants 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.

Cooperative Agreement Terms and Conditions of Award

Not Applicable

When multiple years are involved, awardees will be required to submit the annual Non-Competing Progress Report (PHS 2590 or RPPR) 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)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

Web ticketing system: https://public.era.nih.gov/commonshelp
TTY: 301-451-5939
Email: [email protected]

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)
Telephone: 301-945-7573
TTY: 301-451-5936
Email: [email protected]

Ivana Grakalic, Ph.D.
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Telephone: 301-443-7600
Email: [email protected]

Matthew Reilly, Ph.D.
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Telephone: 301-594-6228
Email: [email protected]

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).

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

Cheryl Nathaniel
National Institute on Drug Abuse (NIDA)
Telephone: 202-526-0108
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 Parts 74 and 92.