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

Background and Rationale

Smoking prevalence among people with schizophrenia is approximately three times that of the general U.S. population, and some reports have estimated cessation rates to be 50% lower. Moreover, this population suffers from significant morbidity and early mortality, with a reduced life expectancy by about 15-25 years compared with the general population. This premature mortality is largely attributable to smoking-related diseases. In fact, a recent cohort study found that tobacco-related conditions comprised an estimated 53% of total deaths among individuals diagnosed with schizophrenia. High rates of co-occurring alcohol and other substance use disorders in schizophrenic populations also contribute to excess morbidity and mortality, and are associated with poorer long-term clinical outcomes.

Unfortunately, most smoking cessation clinical trials exclude individuals with schizophrenia as well as those with alcohol and other substance use disorders. Therefore, in the absence of a critical mass of research, the latest version of the PHS Clinical Practice Guidelines for Treating Tobacco Use and Dependence, recommends that interventions identified as effective for the general population, be applied to this population. However, it is not clear whether treatments that have been shown to aid other groups to quit smoking are also effective for individuals with schizophrenia. Although various combinations of behavior therapy and pharmacotherapy have been shown to be effective, relapse rates in this population remain high. Existing cessation interventions do not approximate the rates produced by the same interventions in the general population; perhaps due to cognitive or sensory deficits, lower task persistence, lower motivation to quit, fewer cessation attempts, increased level of nicotine dependence, and reduced access to treatment. Moreover, beyond their main effects on cessation rates, the mechanisms of action in interventions ranging from bupropion and varenicline to contingency reinforcement are poorly understood, thus limiting scientists ability to improve cessation interventions for this high-risk population.

Given the high rates of smoking, the weak response-rate results, and the medical and economic burden of cigarette smoking in these individuals, better behavioral and pharmacological treatments, designed specifically for people with schizophrenia need to be generated or modified for this population, and tested. Moreover, improved methods to facilitate dissemination and uptake of existing treatments by community practitioners are greatly needed.

Research Objectives

In order to enhance NIH’s efforts to address serious gaps in knowledge on how best to reduce mortality rates among smokers with schizophrenia, this Funding Opportunity Announcement (FOA) seeks to stimulate research on innovative approaches to smoking cessation treatment interventions for people with schizophrenia, with or without co-occurring alcohol or other substance use disorders.

This FOA provides support for grant applications designed to (a) generate novel treatments and improve existing treatments and (b) conduct preliminary tests of novel and improved behavioral, pharmacological, and combined smoking cessation treatments for individuals with schizophrenia by examining the mechanisms of nicotine addiction in individuals with schizophrenia as putative intervention targets. Thus, this FOA facilitates Phased Innovation (R21/R33) applications that focus on Stage I treatment generation and pilot clinical trials that are consistent with an experimental therapeutic approach. Stage I encompasses all activities related to the creation of a new behavioral intervention, or the modification, adaptation, or refinement of an existing intervention (Stage IA), as well as feasibility and pilot testing (Stage 1B). Stage I may involve translational basic to applied (sometimes referred to as T1 ) research. Stage I may also involve the modification or adaptation of interventions for ease of implementation in real-world settings. It can be conducted in: research settings, with research therapists/providers, but it can also be done in real world or community settings, with community therapists/providers. One goal of a Stage I project is to provide necessary materials and information to proceed to a later phase Stage I, Stage II or Stage III project. An equally important goal is to obtain scientific knowledge of the processes that lead to behavior change (i.e., behavioral, cognitive, social or biological change mechanism). Stage I research is iterative and may involve: 1) identifying promising basic or clinical scientific findings relevant to the development or refinement of an intervention; 2) generating/ formulating theories relevant to intervention development and putative change mechanisms; 3) operationally defining, and standardizing new or modified principle-driven interventions; 4) initial or pilot testing of the intervention; 5) experimentally testing the mechanisms and principles of behavior change of the intervention; and 6) as necessary, further refining the intervention. (Additional background on the "Stages " of behavioral intervention development are located in this PA: https://grants.nih.gov/grants/guide/pa-files/PA-13-078.html) This approach requires the identification of a theory-derived target based on putative mechanisms of nicotine addiction in individuals with schizophrenia, and clear hypotheses about how an intervention directed at changing the target can lead to clinical benefits. For the sake of this FOA, target refers to a disorder-maintaining process, which the intervention seeks to modify; target engagement occurs when an intervention in fact modifies this process; target validation occurs when target engagement leads to (or at least correlates with) symptom reduction outcomes; and mechanism of action (how the intervention works) encompasses both target engagement and target validation.

Under this FOA, pilot trials should be designed so that results, whether positive or negative, will provide information of high utility to the field and support decisions about further development and large-scale testing of the intervention.

This FOA provides support for up to two years (R21 phase) for protocol development and target identification and engagement studies, followed by up to 3 years of support (R33 phase) for pilot studies to further evaluate target engagement and its prospective association with clinical benefits and to evaluate the feasibility of conducting a larger trial.

Ultimately, the R33 funding mechanism intends to speed the translation of emerging basic science findings of mechanisms and processes underlying nicotine addiction and schizophrenia into novel intervention approaches that will promote smoking cessation.

Specific Areas of Research Interest

This FOA encourages Phased Innovation (R21/R33) applications that focus on early-stage, treatment generation and pilot clinical trials that are consistent with an experimental therapeutic approach. This approach requires the identification of a theory-derived target based on empirical evidence of mechanisms of nicotine addiction in individuals with schizophrenia with and without alcohol use disorders and other substance abuse comorbidity, and clear hypotheses about how an intervention directed at changing the target can lead to clinical benefits. The target of an intervention is the hypothesized mechanism by which it modifies disease or functional outcomes. Targets can occur at multiple levels from molecular to social processes. Under this FOA, pilot trials should be designed so that results, whether positive or negative, will provide information of high utility to the field and support decisions about further development of the intervention.

Adaptation of interventions with demonstrated efficacy should be undertaken only when justified by a compelling rationale supported by empirical evidence, and where there is a hypothesized target that will be tested within an experimental framework. Examples include, but are not limited to cases where patients with schizophrenia do not adequately respond to an existing smoking cessation treatment protocol and the investigators propose a target for intervention, elucidate a putative mechanism of the proposed intervention, and test whether the intervention affects the target in the hypothesized manner, and delineates the relationship of the target to ultimate outcome.

There is particular interest in the development of interventions that focus on operationally defined, empirically-supported functional domains or symptom(s) of mental disorders as opposed to broad diagnostic categories in which not all subjects may share the same underlying disease process. For example, NIMH Research Domain Criteria (RDoC) constructs may inform mechanism-based hypotheses and the selection of interventions, outcome measures and clinical subjects (see the RDoC webpage http://www.nimh.nih.gov/research-funding/rdoc/nimh-research-domain-criteria-rdoc.shtml for more details). Intervention targets related to RDoC constructs are of interest for this FOA, but other, non-RDoC constructs may be suitable as well, especially if they maximize the probability that subjects share the same mechanism of disorder.

The phased approach supported by this FOA also facilitates more rapid translation by moving promising intervention approaches into pilot studies without requiring an additional grant application, provided that investigators meet the agreed-upon milestones during the R21 phase. Cross-disciplinary research teams may be necessary for successful translation of basic science to clinical application. Applicants are encouraged to leverage existing resources and infrastructure such as those provided by institutions with Clinical and Translational Science Awards (CTSAs) and/or other existing consortia/networks to promote efficient cross-disciplinary collaborations. Cost sharing, including in-kind support, also is encouraged.

Although the R21/R33 mechanism does not require extensive preliminary data, successful applications will propose a theoretically-justified model and empirical support for the mechanism involved in triggering or maintaining the disorder, and a scientific rationale for the proposed treatment target and intervention. Rigorous tests of a target require objective, quantifiable, reproducible measures of target engagement, at behavioral and/or biological levels. These can include measures of structural (e.g., PET receptor occupancy) as well as functional (e.g., performance on a behavioral task, fMRI circuit activation) target engagement. And they can include laboratory tasks that have been previously validated as reflecting underlying behavioral, psychological or neural mechanisms (e.g., go-no-go tasks to measure impulse control, reaction-time to the dot-probe task to measure cognitive attention bias, eye tracking to measure attention, pupil dilation to measure arousal, temporal discount rates to measure self-regulation). Measures of target engagement should be scientifically justified and be as objective and direct as is feasible. Self-report measures can add useful information in a multi-method/multi-measure design that is set to demonstrate construct and convergent validity.

This FOA provides support for up to two years (R21 phase) for preliminary, proof-of-principle studies, that is, studies designed to identify intervention targets, develop the initial protocol, demonstrate target engagement, and explore initial feasibility and tolerability in human participants. This initial phase is followed by up to three years of support (R33 phase) for pilot studies to evaluate the ability of the intervention to impact the hypothesized target and to assess the feasibility of conducting a larger trial to assess the efficacy of the smoking cessation intervention.

The R21 Phase

The R21 phase focuses on intervention generation during which investigators (1) identify an intervention target based on empirical evidence of a mechanism of nicotine addiction in schizophrenia, or mechanism of change for a proposed intervention, (2) generate a preliminary intervention protocol, (3) begin to demonstrate that the intervention alters the targeted mechanism (thus providing an initial proof of principle), and (4) provide preliminary evidence that the intervention can be applied in a clinical population (e.g., in a case series) with adequate acceptability and tolerability to patients. Appropriate activities for the R21 phase may include identification of optimal parameters of the intervention to demonstrate change in the treatment target or mechanism; determination of optimal dose (e.g., level of intensity, session frequency and duration); and/ordevelop and validate measures to demonstrate sensitivity to change in the target or hypothesized mechanism.

Applicants who already have sufficient preliminary data to progress to the R33 phase should apply directly to that FOA PAR-14-231.

Examples of applications seeking to generate and test novel or improved smoking cessation treatments include, but are not limited to:

• Stage IA research aimed at identifying behavioral targets (e.g., cognitive or sensory deficits, working memory, delay discounting, and/or task persistence) and generating interventions designed to modify these targets. This includes preliminary testing to determine if there is target engagement. These novel interventions could be designed to:
  • work as a stand-alone treatment to promote smoking cessation in individuals with schizophrenia with or without alcohol or other substance abuse comorbidities.
  • boost the efficacy to existing interventions to reduce smoking in persons with schizophrenia
  • promote adherence to existing efficacious interventions
• Stage IA research aimed at identifying neurobiological targets (i.e., nicotine receptor deficits, dopamine depletion, etc.) and generating behavioral and/or pharmacological interventions designed to modify these targets. This includes preliminary testing to determine if there is target engagement. These novel interventions could be designed to:
  • work as a stand-alone treatment to promote smoking cessation in individuals with schizophrenia with or without alcohol or other substance abuse comorbidities
  • boost the efficacy to existing interventions to reduce smoking in persons with schizophrenia
  • promote adherence to existing efficacious interventions
• Stage IA research aimed at identifying targets and generating technology-based interventions designed to modify these targets. This includes preliminary testing to determine if there is target engagement. These novel technology-based interventions could be designed to:
  • help an individual, through repeated practice sessions, to modify a target (e.g., attentional bias), believed to be associated with smoking behavior
  • measure smoking behavior and the identified target in real time and enable the smoker to access a technology-based intervention in real time to decrease smoking behavior

The R33 Phase

Funding for the R33 phase is contingent on demonstrating target engagement and initial feasibility in the Stage IA R21 phase in one of the areas described above. The R33 phase supports Stage IB pilot testing of interventions for which the elements of proof-of-principle described above have been demonstrated with sufficient signal of target engagement to justify the proposed pilot study.

The R33 phase is expected to replicate and extend the initial target engagement findings from the R21 phase, and inform the design and implementation of a larger scale study of promising smoking cessation interventions. Research activities in the R33 phase should include further testing of target engagement by testing whether the intervention could cause the hypothesized changes in the target. Additional Stage IB pilot work may include (1) further refining initial manipulations of targeted mechanisms; (2) standardizing the intervention; (3) developing a set of assessment and monitoring procedures designed to assess and sustain the fidelity in which the targets of the intervention are engaged; (4) further testing of the intervention's feasibility, safety and acceptability; (5) testing the association between a change in the target and subsequent outcomes; and (6) evaluating the feasibility of recruitment, retention, and assessments. Stage IB pilot studies are not expected to have sufficient power to conduct a strong test of efficacy.

Examples of Applications of Low Priority

Applications lacking a focus on an experimental therapeutic approach will not be considered a priority for funding. Examples of low priority areas include:

• Pilot studies comparing a novel intervention to other treatment or control conditions in the absence of an experimental approach to target identification, validation, and engagement
• Studies comparing an adaptation of an efficacious treatment to a new patient population in the absence of an experimental approach to target identification, validation, and engagement
• Studies comparing an adaptation of an efficacious treatment to a new patient population in the absence of an empirical rationale for the adaptation target and for the corresponding mechanism by which the adapted intervention or augmentation is expected to substantially enhance outcomes
• Studies that do not identify a putative target
• Studies that do not propose a compelling rationale for a putative target

HIV/AIDS Counseling and Testing Policy for the National Institute on Drug Abuse: In light of recent significant advances in rapid testing for HIV and in effective treatments for HIV, NIDA has revised its 2001 policy on HIV counseling and testing. NIDA-funded researchers are strongly encouraged to provide and/or refer research subjects to HIV risk reduction education and education about the benefits of HIV treatment, counseling and testing, referral to treatment, and other appropriate interventions to prevent acquisition and transmission of HIV. This policy applies to all NIDA funded research conducted domestically or internationally. For more information see https://grants.nih.gov/grants/guide/notice-files/NOT-DA-07-013.html.

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

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

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

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

Higher Education Institutions

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

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

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

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

Other

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

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Applicant Organizations

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

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

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

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

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

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

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

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

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.

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

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

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

The letter of intent should be sent to: NIDALetterofIntent@mail.nih.gov

Applicants are encouraged to send the letter of intent by email to the email address above but as an alternative the letter may also be sent to:

Director - Smoking and Schizophrenia PAR
Office of Extramural Affairs
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 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.

The R21 and R33 cannot be funded in the same fiscal year.

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

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

Research Strategy:

Applicants must include an operational definition and objective, valid measures of the intervention’s target (change mechanism). All applicants should provide a compelling scientific rationale for any measures proposed to assess the link between the hypothesized mechanism/target and clinical effect. Applicants should delineate how the intervention approach is grounded in empirical evidence of mechanism of disorder, mechanism of treatment effect, or mediators and moderators of treatment response For studies of pharmacological interventions, a clear description should be included of the approach for determining pharmacological dose\response relationships and target engagement of the drug candidate.

Applicants should justify the need for the R21 phase. Applicants should specify the measurement schedule and data and analytic strategies for results obtained during the Stage IA R21 phase. The description of the R21 phase should include milestones that, if met, will justify taking the proposed intervention into a Stage IB pilot study. Before proceeding to Stage IB R33 phase, applicant must provide evidence that (a) the intervention engages that target, including demonstration that the intervention engages and alters the target at the level of receptors, circuits, behaviors, or psychological/cognitive/affective processes and (b) provide preliminary evidence that the intervention can be applied in a clinical population with adequate acceptability and tolerability to patients.) A discussion of how the milestones achieved in the Stage IA R21 phase will inform a Stage IB R33 pilot study should be included. The applicant should specify conditions under which they would not proceed to the R33 phase.

Description of the Stage IB R33 phase should include indicators that will be used at the completion of the pilot study to inform whether the target is valid and the intervention is feasible and promising for evaluation of efficacy in a larger clinical trial.

The description of the R33 phase should include a definitive demonstration of target engagements and change of the targeted mechanism in the hypothesized direction. In addition, applicants should propose concrete indicators of feasibility of taking the proposed intervention to a larger clinical trial of efficacy, and should describe how these indicators will be used to inform the next phase of intervention development. Appropriate indicators may include, but are not limited to, a predetermined number of sessions attended, completion of activities outside of the clinic ("homework"), demonstration that assessment instruments are sensitive to change in the treatment target or symptom, measures of patient satisfaction, reports of adverse events, and an a-priori definition of what would constitute preliminary evidence that changes in targets are associated with increase smoking cessation or reduction. These are examples only; goals and feasibility milestones/indicators must be specific to the proposed intervention.

The clarity and completeness of the R21/R33 application with regard to specific goals and feasibility milestones/indicators are critical.

The applicant should propose milestones in the form of quantitative criteria that are pre-specified and rigorously defined to assess milestone achievement and operational feasibility relevant to advancing from the R21 to the R33 phase. These R21 milestones should be feasible, well developed and quantifiable with regard to the specific aims of each stage. A feasible timeline should be proposed. Clear measures of success should be defined that (a) demonstrate that the intervention alters the targeted mechanism (thus providing an initial proof of principle), and (b) provide preliminary evidence that the intervention can be applied in a clinical population with adequate acceptability and tolerability to patients.

The applicant should specify conditions under which they would not proceed to the R33 phase. Milestones representing clearly defined aims for the R33 phase should also be proposed. These milestones should be feasible, well developed and quantifiable with regard to the specific aims. A feasible timeline should also be proposed. Feasible plans for sample size and timely recruitment of subjects should be delineated. A clear strategy for tracking recruitment and facilitating retention should be proposed.

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

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 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 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.

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?

Does the investigative team include methodological expertise in the study and measurement of change mechanisms?

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?

Is the need for the R21 phase justified? Does the R21 application include valid (or procedures to develop and validate) measures of target identification and engagement, and are the proposed methods appropriate to determine milestones for taking the intervention a step further to the pilot study?

Is the intervention approach grounded in empirical evidence of mechanism of disorder, mechanism of treatment effect, or mediators and moderators of treatment response?Is the study proposed in the R33 phase designed to measure the prospective association between target engagement and clinical outcomes? Will the results of the proposed study provide information that will inform the design and implementation of a larger efficacy trial if the intervention looks promising?

Milestones and Timeline: R21 Milestones:

Are quantitative criteria pre-specified and rigorously defined to assess milestone achievement and operational feasibility relevant to advancing from the R21 to the R33 phase?

Are R21 milestones feasible, well developed and quantifiable with regard to the specific aims of each stage?

Is the timeline feasible? Specifically, will the investigators and NIH Program Officials be able to determine if the project succeeded in (a) demonstrating that the intervention alters the targeted mechanism (thus providing an initial proof of principle), and (b) providing preliminary evidence that the intervention can be applied in a clinical population with adequate acceptability and tolerability to patients?

Does the application specify conditions under which they would not proceed to the R33 phase?

Milestones and Timeline: R33 Phase:

Are appropriate, evaluative milestones clearly defined for the aims associated with the R33 phase?

Are R33 milestones feasible, well developed and quantifiable with regard to the specific aims? Is the timeline feasible?

Are the plans for sample size and timely recruitment of subjects feasible? Is there a clear strategy for tracking recruitment and facilitating retention?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of children, justified in terms of the scientific goals and research strategy proposed?

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 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.

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 National Institute on Drug Abuse 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.

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.

Prior to funding an application, the Program Officer will contact the applicant to discuss the proposed milestones and any changes suggested by the review panel as indicated in the Summary Statement. The Program Officer and the applicant will negotiate and agree on a final set of R21 milestones.

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.

The Project Director/Principal Investigator (PD/PI) will submit a progress report to the Program Officer upon completion of the R21 milestones. Receipt of this progress report will trigger an administrative program review that will determine whether or not the R33 should be awarded. The release of R33 funds will be based on successful completion of negotiated scientific milestones, on program priorities, and on the availability of funds. In addition, the final report for the R33 should include go/no-go indicators of target engagement and indicators of feasibility of taking the proposed intervention to a larger clinical trial of efficacy.

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)

Finding Help Online: https://grants.nih.gov/support/index.html

TTY: 301-451-5939
Email: commons@od.nih.gov

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

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone: 301-945-7573
TTY 301-451-5936
Email: GrantsInfo@nih.gov

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

Peter Muehrer, Ph.D
National Institute of Mental Health (NIMH)
Telephone: 301- 443-4708
Email: pmuehrer@mail.nih.gov

Yvonne Hunt, Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276-6975
Email: huntym@mail.nih.gov

Joanne Fertig, Ph.D
National Institute of Alcohol Abuse and Alcoholism (NIAAA)
Telephone: 301- 443-0635
Email: jfertig@mail.nih.gov

Mark Swieter, Ph.D.
National Institute on Drug Abuse (NIDA)
Telephone: 301-435-1389
Email: mswieter@mail.nih.gov

Diana Haikalis
National Institute on Drug Abuse (NIDA)
Telephone: 301-435-1373
Email: dhaikali@nida.nih.gov

Rita Sisco
National Institute of Mental Health (NIMH)
Telephone: 301-443-2805
Email: siscor@mail.nih.gov

Carol Perry
National Cancer Institute (NCI)
Telephone: 240-276-6282
Email: perryc@mail.nih.gov

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

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92.