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

Polysubstance use (PSU) is defined as the use of two or more addictive drugs simultaneously or concurrently. Simultaneous PSU is characterized by the use of multiple drugs at the same time whereas concurrent PSU refers to the use of multiple substances within a specified period of time, but not simultaneously. Polydrug users report that the simultaneous ingestion of two addictive substances can produce additive/synergistic euphoric effects and concurrent use is intended to alleviate the negative consequences of another drug. For example, the co-administration of heroin and cocaine, otherwise known as speedballing, produces enhanced reinforcing effects when compared to the delivery of either drug alone. Alternatively, benzodiazepines, opioids, or alcohol are commonly used to relieve the aversive symptoms during a cocaine crash, an anhedonic state that is characterized by general dysphoria, agitation, and anxiety.

Epidemiological data from national surveys indicate that approximately 20% to 30% of youth and young adults engage in PSU and the majority of treatment seekers are polysubstance abusers. Polydrug users initiate drug use at an earlier age than single drug users, and PSU occurs more frequently in males. Compared to users of a single drug, polysubstance users exhibit more mental health problems, are more likely to misuse or abuse prescription drugs, are at a greater risk for health complications and overdose, and are more likely to report a higher rating on the Addiction Severity Index. Moreover, polysubstance abuse and addiction are associated with a number of social disadvantages including elevated risk of academic failure and non-completion, higher frequency of employment and legal issues, and a greater likelihood of engaging in physical violence. Together, these data suggest that PSU occurs more commonly in the drug using population and is associated with worse health and societal consequences than single drug use.

While clinicians and epidemiologists have long recognized that PSU is prevalent among drug users, this real-world context has not been fully investigated in basic animal and human research. The integration of PSU into human and animal basic research is hampered by the need for additional control groups, the complexities of data interpretation, and the challenges of modeling human phenomena with animal research. Limited investigations of PSU in basic science research hinder a full exploration and comprehension of the underlying processes and mechanisms that subserve poorer health and social outcomes that are associated with this pattern of use. This FOA will address this knowledge gap by requiring a translational component in the research proposals in order to encourage applicants to identify similarities and differences between PSU and single drug use with a broader perspective.

Collaborative Research on Addiction (CRAN) is a National Institutes of Health (NIH) partnership between the National Institute on Alcohol Abuse and Alcoholism (NIAAA), the National Institute on Drug Abuse (NIDA), and the National Cancer Institute (NCI). The mission of CRAN is to provide a strong collaborative framework to leverage resources and expertise that will meet public health needs by broadening the research focus of participating institutes to better address poly- or multiple substance use, abuse, and addiction. To this end, the purpose of this FOA is two-fold: (1) to compare the similarities and differences between PSU and single drug use across antecedent and consequential behavioral, neurobiological, genetic, and epigenetic changes; and (2) to rapidly integrate findings along a translational pipeline, consisting of basic science research in animals, human-based laboratory investigations, and epidemiological studies. The goal of this initiative is to support investigations on tobacco, alcohol, marijuana, and other licit and illicit drugs of abuse. Applicants should focus on two primary drugs of abuse to facilitate the integration of findings and aid interpretability, with the understanding that the human condition often involves the use of multiple substances. The intent of this announcement is NOT to support other behavioral addictions, such as food addiction, gambling, or internet/gaming addictions.

PSU findings from one stage of the translational trajectory are rarely integrated into another stage. For this reason, this funding announcement will utilize a R21/R33 mechanism to facilitate the integration of findings along the translational continuum in a timely manner. The R21 phase of the application can originate in any of these three stages along the translational trajectory, consisting of basic science research in animals, human-based laboratory investigations, and epidemiological studies. These findings will be back or forward translated to another stage during the R33 phase and will assist in bridging the translational gap. This mechanism is intended to encourage our investigators to examine drug abuse and addiction with a broader perspective, leveraging the insights gleaned from one stage during the R21 phase to guide and stimulate integrative science across the translational pipeline during the R33 phase. Moreover, the structure of this funding mechanism will capitalize on the many advantages that are found along the translational trajectory while providing an opportunity to address the limitations and challenges that exist within each of these three translational stages. For example, while humans who are addicted to drugs can provide rich, multi-dimensional data that are not attainable in animal models, it is often difficult to ascertain if the outcomes observed in humans stem from drug abuse or other pre-existing conditions. Hence, the back-translation of findings from the clinic into animal models provides a unique opportunity to address this caveat and permits researchers to identify behavioral, psychological, social, and neurobiological mechanisms under strict experimental control. Collectively, the data gathered from both human and animal research will enrich our understanding of PSU and any related outcomes.

Programmatic assessment of accomplished milestones achieved during the R21 phase will guide the decision to determine if advancement to another translational stage in the R33 phase of the application will be granted. It is not expected that all applications will continue to the R33 phase. Due to the integrative nature of this FOA, it is recommended that applicants form integrative teams to oversee these two phases and discuss applications in advance with NIH program experts. It is expected that the PSU data gathered during these R21 and R33 phases will serve as preliminary data for future NIH applications on this topic.

Studies may begin in any stage along the translational trajectory described herein, consisting of basic animal research, human-laboratory or field-based investigations, or epidemiological studies. All projects should include the following:

• Clear milestones for the R21 phase and related scientific goals for the R33 phase.
• The R33 portion of the application should focus on a translational stage that is different from the R21 phase.
• A unifying and testable hypothesis that will be examined during both the R21 and R33 phase.
• Applications should include a polysubstance group and, whenever possible, single-drug control groups should be included to determine if the outcomes observed in the PSU group are unique to combined drug use. It is not required to collect new data on single drug consequences if appropriate and comparable prior data already exist. Evidence of these data should be provided in the application.
• Investigation of two primary drugs of abuse. The intent of this announcement is NOT to support other behavioral addictions, such as food addiction, gambling, or internet/gaming addictions.
• Demonstration that feasibility of data collection and analysis is possible within the budget and time constraints for both phases.

Examples of milestones for the R21 phase include, but are not limited to:

• Secondary data analysis of existing epidemiology, imaging, or human behavioral data sets to identify significant differences between patterns of PSU and single drug use and their outcomes.
• Analysis of existing biological samples/specimens to characterize changes in biomarkers of PSU vs single drug use.
• Identification of patterns of polydrug use in humans in order to guide experimental approaches in animal research or laboratory studies with human subjects.
• Exploration of differences between PSU and single drug use trajectories and/or health outcomes in animal models or ongoing human-based laboratory studies.

The objectives for the R33 phase should be based, at least in part, on findings from the R21 phase. Examples of appropriate goals for the R33 phase include, but are not limited to:

• Establishment of an animal model of PSU based on data from the R21 phase.
• Replication and validation of the PSU phenomena observed in the R21 phase in a different translational stage.
• Characterization of social, behavioral, cognitive, epi/genetic or biological mechanisms based on findings from the R21 phase.
• Incorporation of new question items into ongoing epidemiological surveys that are based on findings from basic or clinical data collected during the R21 phase.
• Recruitment of additional PSU participants in ongoing imaging and/or behavioral studies in a laboratory setting based on animal or epidemiological data generated during the R21 phase.

Epidemiological data indicate that PSU is associated with worse health and social outcomes than single drug use. Hence, the intent of this announcement is to identify the underlying mechanisms and processes that mediate this vulnerability. Additionally, the structure of this mechanism will allow for more direct and timely communication of findings along a translational continuum, consisting of basic science research in animals, human-based laboratory studies, and epidemiological investigations. To facilitate the translation of findings, applicants should focus on two primary drugs of abuse in research supported by this FOA, with the understanding that multiple compounds are used in human abusers. Whenever possible, applicants should relate the outcomes of PSU to single drug use to determine if the findings observed under the PSU condition are distinct from those found under conditions of single drug administration. The comparison of PSU groups to valid pre-existing data sets of single drug consequences is acceptable, but these data sets should be included in the application. Examples of topics where integration of data across the translational stages that can be proposed in the application include, but are not limited to:

• Health outcomes, such as changes in cancer biomarkers, immune function, toxicity
• Differences between sequential or concurrent patterns of drug use
• Developmental differences in patterns of use or combinations
• Synergistic vs additive neuroadaptations that occur in PSU
• Trajectories of or influences on relapse incidence and/or rates
• Social factors involved in PSU versus single drug use trajectories
• Vulnerable or resilient phenotypes and/or genotypes that predict PSU or response to treatment
• Differences in treatment strategies (i.e., examine if treatment of one substance improves PSU treatment or if treatment of both substances is the most effective course of action)
• Prevention/intervention strategies for PSU
• PSU in vulnerable populations (e.g., neonatal exposed individuals, adolescents, aging populations)
• Sex differences in the acquisition, maintenance, relapse, or treatment of PSU
• Measures of antecedent or consequential cognitive, affective, or motivational processes in PSU
• Identification of molecular pathways, neural circuitry, and neurotransmitter systems that mediate PSU
• Accelerated transition to compulsive drug use under different drug use conditions or patterns
• PSU-induced epigenetic modifications

The intent of this initiative is NOT to address gateway hypotheses. However, applications that contribute to the understanding of concurrent vs sequential contexts are encouraged. Additionally, the goal of this announcement is NOT to support other behavioral addictions, such as food addiction, gambling, or internet/gaming addictions.

Please note that some of the experimental approaches to modeling PSU and PSU outcomes may not have a direct counterpart across translational stages. For example, it may be difficult to capture the complete drug history profile of human users in animal models, such as the drug dose, lifetime use, comorbid psychiatric conditions, or the route of administration. Additionally, laboratory assessments that examine motivational or cognitive processes in humans may not have an exact complement in animals and effects seen in animals may not always be assessed in the same manner in humans. Investigators should utilize the best animal model and procedure to replicate the observed phenomena in humans. Compromises in experimental approaches and modeling should be made and are needed in order to facilitate the translation of outcomes. For example, it would be appropriate to examine relapse rates in epidemiological surveys, and then to translate this approach by measuring drug craving in humans and/or examining reinstatement of operant responding in animals. Whenever possible, investigators are encouraged to use the assessments and models that have the most translational potential.

Applicants should provide a description of how the study designs, methods and assessments are complimentary such that outcomes at one translational stage enhance the interpretation of outcomes at the other translational stage.

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

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

Higher Education Institutions

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

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

o Hispanic-serving Institutions

o Historically Black Colleges and Universities (HBCUs)

o Tribally Controlled Colleges and Universities (TCCUs)

o Alaska Native and Native Hawaiian Serving Institutions

o Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)
• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations
• Non-domestic (non-U.S.) Entities (Foreign Institutions)

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

Applicant Organizations

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

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

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

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

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

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

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

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

The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101).

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

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

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

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

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

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

The letter of intent should be sent to: [email protected].

Office of Extramural Policy and Review

National Institute on Drug Abuse/NIH/DHHS
6001 Executive Boulevard, Suite 4243, MSC 9550
Bethesda, MD 20892-9550

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

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

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

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

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

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

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

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

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

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

Specific Aims: Separate specific aims should be presented for the R21 and R33 phases.

Research Strategy: The Research Strategy should contain separate sections that describe both the R21 and R33 phases, as appropriate. Separate research design and methods could be presented as needed for the R21 and R33 phases. It is not necessary to repeat information or details in the R33 section that are described in the R21 section.

Any preliminary data that will support or justify the proposed hypothesis, rationale or development plan may be included. However, preliminary data are not required for an R21/R33 application.

Some of the experimental approaches to modeling PSU and PSU outcomes may not have a direct counterpart across translational stages. For example, it may be difficult to capture the complete drug history profile of human users in animal models, such as the drug dose, lifetime use, comorbid psychiatric conditions, or the route of administration. Additionally, laboratory assessments that examine motivational or cognitive processes in humans may not have an exact complement in animals and effects seen in animals may not always be applicable to humans. Whenever applicable, investigators should describe the most appropriate animal model and procedure to replicate the observed phenomena in humans. Compromises in experimental approaches and modeling should be made and are needed in order to facilitate the translation of outcomes. For example, it would be appropriate to examine relapse rates in epidemiological surveys, and then to translate this approach by measuring drug craving in humans and/or examining reinstatement of operant responding in animals. Whenever possible, investigators are encouraged to describe the assessments and models that have the most translational potential.

Applicants should provide a description of how the study designs, methods and assessments are complementary such that outcomes at one translational stage enhance the interpretation of outcomes at the other translational stage.

Since the intent of this announcement is to leverage PSU findings from one phase of the translational trajectory to guide research in another phase, PDs/PIs are not required to provide evidence of prior collaborative relationships. However, the PDs/PIs of both phases should describe a plan to communicate findings with each other throughout the life of the grant.

Milestones and R21/R33 Transition

The application must include milestones that are expected to be achieved by the end of the R21 phase. Milestones should be specific, quantifiable, and scientifically justified; they should not be simply a restatement of the specific aims for the R21 phase.

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.

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 our Post Submission Application Materials policy.

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/R33 phased innovation grant supports investigation of novel scientific ideas or new interventions, model systems, tools, or technologies that have the potential for significant impact on biomedical or behavioral and social sciences research. An R21/R33 grant application need not have preliminary data, extensive background material or preliminary information; however, they may be included if available. Appropriate justification for the proposed work can be provided through literature citations, data from other sources, or, when available, from investigator-generated data. Accordingly, reviewers will focus their evaluation on the conceptual framework, the level of innovation, and the potential to significantly advance our knowledge or understanding. Reviewers will assign a single impact score for the entire application, which includes both the R21 and R33 phases.

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? If the PDs/PIs do not have a prior collaborative relationship, do the investigators of both phases have an adequate plan to communicate findings with each other throughout the life of the grant?

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?

Does the application include investigations in two different stages in the translational pipeline, which are composed of basic science research in animals, human-based laboratory studies, and epidemiological investigations? . Is there a unifying and testable hypothesis that transcends both R21 and R33 phases? Does the application provide clear milestones for the R21 phase and related scientific goals for the R33 phase? Are those milestones conducive to accomplishing the study aims? Are the goals of the R33 phase based, in part, on findings collected during the R21 phase? Is the proposal feasible within the budget and time constraints for both R21 and R33 phases?

When there are differences in species, study designs, methods and assessments across the R21 and R33 phases, does the application provide a description of how the studies are complimentary such that the outcomes at one translation stage will enhance the interpretation of outcomes at the another translational stage? If the intent of the application is to replicate the PSU phenomenon across translational stages, do the PD/PIs provide a description of how differences in research approaches are complimentary across species and study design? If either the R21 or R33 phase proposes to use animal models, do the investigators utilize the most appropriate animal model or procedure to mimic outcomes observed in humans? Whenever applicable, does the application include single-drug controls or prior valid data on single drug outcomes to determine if changes observed in the PSU group are unique to combined drug use?

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

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

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

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

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

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

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

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

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by 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 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. Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Board. The following will be considered in making funding decisions:

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

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

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

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

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.

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 http://www.hhs.gov/ocr/civilrights/resources/laws/revisedlep.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 http://www.hhs.gov/ocr/civilrights/understanding/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 http://www.hhs.gov/ocr/office/about/rgn-hqaddresses.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

Cooperative Agreement Terms and Conditions of Award

Not Applicable

When multiple years are involved, awardees will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

A final progress report, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

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

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

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-945-7573

Shelley Su, Ph.D.
National Institute on Drug Abuse (NIDA)
Telephone: 301-402-3869
Email: [email protected]

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

Glen Morgan, Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276-6787
Email: [email protected]

Maribeth Champoux, Ph.D.
Center for Scientific Review (CSR)
Telephone: 301-594-3163
Email: [email protected]

Christine Kidd
National Institute on Drug Abuse (NIDA)
Telephone: 301-443-6710
Email: [email protected]

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

Carol Perry
National Cancer Institute (NCI)
Telephone: 240-276-6282
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.