Participating Organization(s)	National Institutes of Health (NIH)
Components of Participating Organizations	National Institute of Mental Health (NIMH) National Institute on Aging (NIA) National Institute on Alcohol Abuse and Alcoholism (NIAAA) National Institute on Drug Abuse (NIDA)
Funding Opportunity Title	Development and Application of PET and SPECT Imaging Ligands as Biomarkers for Drug Discovery and for Pathophysiological Studies of CNS Disorders (R21/R33)
Activity Code	R21/R33 Phased Innovation Award
Announcement Type	Reissue of PAR-10-024
Related Notices	NOT-OD-16-004 - NIH & AHRQ Announce Upcoming Changes to Policies, Instructions and Forms for 2016 Grant Applications (November 18, 2015) NOT-OD-16-006 - Simplification of the Vertebrate Animals Section of NIH Grant Applications and Contract Proposals (November 18, 2015) NOT-OD-16-011 - Implementing Rigor and Transparency in NIH & AHRQ Research Grant Applications (November 18, 2015) June 3, 2014 - Notice NOT-14-074 supersedes instructions in Section III.3 regarding applications that are essentially the same. August 21, 2013: Removed reference to ASSIST in section IV.3, since ASSIST is currently only available for multi-project applications. July 24, 2013 - See Companion PAR-13-282 Development and Application of PET and SPECT Imaging Ligands as Biomarkers for Drug Discovery and for Pathophysiological Studies of CNS Disorders (R21). May 30, 2013 (NOT-OD-13-074) - NIH to Require Use of Updated Electronic Application Forms for Due Dates on or after September 25, 2013. Forms-C applications are required for due dates on or after September 25, 2013.
Funding Opportunity Announcement (FOA) Number	PAR-13-158
Companion Funding Opportunity	PA-13-157, R21 Exploratory/Developmental Grant PAR-13-282, R21 Exploratory/Developmental Research Grant
Number of Applications	See Section III. 3. Additional Information on Eligibility.
Catalog of Federal Domestic Assistance (CFDA) Number(s)	93.242, 93.866. 93.273, 93.279
Funding Opportunity Purpose	This Funding Opportunity Announcement (FOA) invites research grant applications from organizations/institutions that propose the development of novel radioligands for positron emission tomography (PET) or single photon emission computed tomography (SPECT) imaging in human brain, and that incorporate pilot or clinical feasibility evaluation in pre-clinical studies, model development, or clinical studies.

Posted Date	March 25, 2013
Open Date (Earliest Submission Date)	May 16, 2013
Letter of Intent Due Date(s)	Not Applicable
Application Due Date(s)	Standard dates apply, by 5:00 PM local time of applicant organization. Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.
AIDS Application Due Date(s)	Not Applicable
Scientific Merit Review	Standard dates apply
Advisory Council Review	Standard dates apply
Earliest Start Date	Standard dates apply
Expiration Date	May 8, 2016
Due Dates for E.O. 12372	Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

Part 1. Overview Information
Part 2. Full Text of the Announcement
Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

The purpose of this Funding Opportunity Announcement (FOA) is to facilitate the development of PET and SPECT probes for molecular targets that are implicated in the pathophysiology of brain and behavioral disorders (e.g., receptors, intracellular messengers, disease-related proteins). The use of radiotracers for imaging molecular events in preclinical and clinical studies is essential for understanding the circuitry that underlies normal brain function and the pathophysiology of brain disorders. The long-term goal of this FOA is to facilitate the broad application of neuroimaging probes that are fit-for-purpose for their intended use in pathophysiological studies, drug discovery/development research, or biomarker development/qualification studies as quantifiable indicators of disease progression and treatment efficacy.

Tremendous opportunities exist for the application of PET and SPECT imaging in studies of the pathophysiology and treatment of brain disorders, but relatively few radioligands are currently available for functional imaging of target molecules implicated in normal brain function, aging, and in brain and behavioral disorders. Increasing the availability of PET and SPECT radiotracers will aid in: a) understanding the abnormal biological processes which underlie mood disorders and other brain disorders; b) determining the interaction of a drug or drug candidate with a specified target; c) guiding initial dosing of new therapeutic agents; and d) identifying central biomarkers of the illness, with the potential to predict symptom onset, monitor the progression of the disease, and assess the efficacy of therapeutic compounds.

This FOA is intended to stimulate the development of radioligands for molecular targets (e.g., receptors, cell adhesion molecules, intracellular messengers, and disease related proteins) that are of broad interest to the scientific community. The widespread availability and use of these radioligands are expected to: 1) accelerate research on identifying and characterizing the neural circuits and pathways implicated in the pathophysiology of brain disorders (especially mental and behavioral disorders, substance abuse, neurodegenerative disorders, and pediatric brain disorders) and brain changes with age, and 2) facilitate the identification of new therapeutic targets and the development of new compounds as potential therapeutic agents. Research partnerships among investigators in both academia and pharmaceutical and biotechnology industries are encouraged to more rapidly develop PET and SPECT radiotracers and apply neuroimaging in drug discovery, biomarker development/qualification, and pathophysiological studies.

• The proposed development of a radioligand (agonist, antagonist, or allosteric modulator) for a molecular target or for a radioimaging probe to monitor changes in a cellular process should be well-justified and the resulting radiotracer fit for the intended purpose. There is limited interest, without compelling justification, in another tracer of the same class of targets listed in the CNS Radiotracer Table, or in another tracer for targets in which a radioligand development effort is underway in the pharmaceutical industry.
• The preponderance of tracers for molecular targets developed and utilized to date fall into the pharmacologic class of orthosteric antagonists with the most notable exceptions being ligands for benzodiazepine and opiate receptors (see http://www.nimh.nih.gov/research-funding/therapeutics/cns-radiotracer-table.shtml). Our understanding of the relationship between occupancy and downstream effects of agonists and allosteric modulators is still at an early stage such that ligands that would enable more in depth exploration of such relationships would be of particular interest, especially for those neurotransmitter targets that represent opportunities for novel drug discovery (e.g., metabotropic and ionotropic glutamate receptor subtypes; see http://www.iom.edu/Reports/2011/Glutamate-Related-Biomarkers-in-Drug-Development-for-Disorders-of-the-Nervous-System.aspx).
• In addition to PET tracers for potential therapeutic molecular targets, there is interest in tracers that bind to targets that can be used to monitor changes in cellular processes that are linked to brain plasticity or pathophysiology (e.g., neuroinflammation, neurogenesis, mitochondrial function). For instance, markers of microglial activation would fall into this class as would any binding site alteration that could be linked to neurodegenerative processes. Applications to develop these classes of tracers that are not amenable to validation with existing pharmacologic tool compounds should include description of a feasible validation path (e.g., differences in binding as a function of degree of brain pathology such as is the case for PiB (Pittsburgh compound B) or florbetapir measures of amyloid load in Alzheimer’s Disease).
• Prioritization of molecular targets for ligand development is an ongoing exercise and interested parties are encouraged to contact one of the NIH Scientific/Research Contacts to discuss the perceived level of need for a particular PET tracer.

The following objectives would make appropriate topics for proposed R21/R33 projects. This list is not meant to be all-inclusive.

• Lead compound identification/development and syntheses of chemicals with suitable binding affinity, biodistribution, pharmacokinetics, and physiochemical properties allowing radiochemical synthesis.
• Pre-clinical studies, including: initial pharmacology and toxicology to screen out compounds that are unlikely to be promising candidates for PET or SPECT imaging; radiolabeling procedures; in vitro and ex vivo autoradiography; in vivo imaging including micro PET (rodent and/or primate); and studies of pharmacological specificity, biodistribution, and pharmacokinetics.
• Determination of toxicology (FDA approved) for submission of an exploratory Investigational New Drug (IND) application or IND application.
• Exploratory IND or IND application development and submission to the FDA prior to pilot human studies.
• Pilot human imaging studies with normal controls, pharmacological challenges with analyses of radiometabolites under the auspices of IRB approval (e.g., exploratory IND or IND development and submission).
• Pilot studies of the PET or SPECT radiotracer in patient/disease populations to assess its utility for research in pathophysiology, drug discovery, or biomarker development.

The development and strengthening of partnerships between scientists from academia and the pharmaceutical industry is a highly desirable outcome of this FOA and is strongly encouraged. Pharmaceutical scientists are encouraged to actively participate as Program Director/Principal Investigator (PD/PI) or key personnel/collaborator in the R21 and/or the R33 phase of the project.

Funding Instrument	Grant: A support mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity.
Application Types Allowed	New Resubmission Revision The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.
Funds Available and Anticipated Number of Awards	The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications.
Award Budget	Direct costs are limited to a maximum of $175,000 per year for the R21 phase and less than $500,000 per year for the R33 phase.
Award Project Period	The total project period for a combined R21/R33 application submitted in response to this FOA may not exceed five years, with no more than three years for either the R21 phase or the R33 phase.

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

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

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

Other

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

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

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

Applicant Organizations

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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 instruction:

• The R21/R33 Phased Innovation Award application must be submitted as a single application with one Research & Related Budget component.
• Budget Justification: For each budget year, indicate if the requested budget is for the R21 phase or the R33 phase.
• 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 instruction:

• The R21/R33 Phased Innovation Award application must be submitted as a single application with one PHS398 Cover Page Supplement component.

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

Research Strategy:

Applicants must include the following information as part of the research strategy:

1. Provide a strong justification for why a radiotracer is needed for the target (see http://www.nimh.nih.gov/research-funding/therapeutics/cns-radiotracer-table.shtml).

2. Address the feasibility of developing a radiotracer for the target: the density and affinity of the tracer target in brain region(s) of interest in post-mortem human brain) must be conducted, or reference to such information in the published literature, before initiation of a tracer discovery project.

3. State a plan for achieving the desired properties for the radiotracer (see considerations below).

Critical considerations for lead compound identification, development, and synthesis:

1. Feasibility based on the density and affinity of the tracer target in brain region(s) of interest in post-mortem human brain).

2. Affinity, lipophilicity, and target selectivity

a. Bmax/Kd > 5 in human subjects

b. Lipophilicity: logD (ideally ~ 2)

c. Target selectivity in brain region of interest; appropriate for proposed context of radiotracer use

3. Delivery: adequate penetration of blood-brain barrier with standardized uptake values (SUV) > 2 in the brain regions of interest, without influence by ABC efflux transporters;

a. Lack of substrate for ABCB1 (P-glycoprotein) or ABCG2 (BCRP)

4. Amenability to labeling with 11C or 18F and metabolic stability of the label (e.g.,18F label is in a metabolically stable position)

5. Amenability to production: radiochemical yield (%); practical yield (MBq); specific activity

6. Specific binding: sufficient binding potential (BP) or volume of distribution (BP > 2) to assess target occupancy by drugs or to characterize CNS pathophysiology

Considerations for in vivo assessment of a PET radiotracer candidate:

1. Lack of radiometabolites: within brain, or of [18F]fluoride ion in skull

2. Amenability to accurate quantification: e.g., stable total distribution volume (VT) within scan session

3. Time-activity curves for brain and plasma

4. Robust test-retest reliability: < 10% by variation

5. Compartmental modeling with arterial input function

Specific Instructions for Preparing a Combined R21/R33 Phased Innovation Award Application

Within the Research Strategy, applicants should describe both the R21 phase and the R33 phase, including milestones.

The milestones proposed in the application should be well described, quantifiable, and scientifically justified to allow program staff to assess progress in the R21 phase. The milestones will be evaluated by the Scientific Review Group. A discussion of the milestones relative to the progress of the R21 phase and the implications of successful completion of the milestones for the R33 phase should be included. The clarity and completeness of the R21/R33 application with regard to specific goals and feasibility milestones are critical.

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

• Applications are expected to include a plan to share protocols, procedures, unlabeled PET and SPECT ligands, analytical tools, IND filing information, and other materials that may be developed in the course of the project with the scientific community.
• Applicants are invited to utilize NIH supported repositories such as the NIMH Chemical Synthesis and Drug Supply Program (http://nimh-repository.rti.org//) or the NIDA Drug Supply Program to make unlabeled PET and SPECT ligands widely available to the scientific community.
• Applicants are invited to utilize NIH supported databases such as the NIMH/Society for Non-Invasive Imaging in Drug Development (SNIDD) Tracer Database (http://kidb.bioc.cwru.edu/snidd/) or the NIH Roadmap Molecular Imaging and Contrast Agent Database (http://www.ncbi.nlm.nih.gov/bookshelf/corehtml/pmc/homepages/bookshelf/micad.html) to enable centralized access to and dissemination of imaging radiotracer information (e.g., protocols, methodologies, toxicology, safety, dosimetry, IND-filing) prior to or at the time of publication

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.

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 the instructions for post-submission materials, as described in NOT-OD-10-115.

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:

For the R21/R33 Phased Innovation Award application, the Scientific Review Group will evaluate the specific goals for each phase and the feasibility milestones that would justify expansion to the R33 phase. A single impact/priority score will be assigned to each discussed application. For the R21/R33 application the initial review group may recommend that only the R21 phase be supported, based on concerns related to the application’s specific goals and the feasibility milestones justifying the expansion to the R33 phase. Deletion of the R33 phase by the review panel or presentation of inadequate milestones in the application may affect the merit rating of the application.

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? Is there a compelling justification for the development of a radiotracer for the target or cellular process and its intended use?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

Innovation

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

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Is there evidence of feasibility that the target can be detected in the brain region(s) of interest with a radiotracer? Are the desired properties for the radiotracer clearly stated and reasonable for the proposed target? Is there a clearly delineated plan for achieving the desired properties for the radiotracer?

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

Environment

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

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

Milestones

Are the milestones quantitative? Are the proposed milestones appropriate and sufficient for assessing progress and judging the success of the R21 work? Are the proposed milestones appropriate and sufficient to allow an assessment of whether the R33 phase should be awarded? Do the milestones establish feasibility for all aspects of the proposed R33 work?

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 Human Subjects Protection and Inclusion Guidelines.

Inclusion of Women, Minorities, and Children

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

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), 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. 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.
• Program staff will be responsible for the administrative review of the proposed milestones and the plan for sharing research resources. The adequacy of the proposed milestones and of the resources sharing plan will be considered by Program staff of the funding organization when making recommendations about funding applications. Program staff may negotiate modifications of the proposed milestones and of the data and resource sharing plans with the awardee before recommending funding of an application. The final version of the milestones and of the data and resource sharing plans negotiated by both will become a condition of the award of the grant.

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons.

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

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

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

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

Any application awarded in response to this FOA will be subject to the DUNS, SAM Registration, and Transparency Act requirements as noted on the Award Conditions and Information for NIH Grants website.

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

Cooperative Agreement Terms and Conditions of Award

Not Applicable

When multiple years are involved, awardees will be required to submit the annual Non-Competing Progress Report (PHS 2590 or RPPR) and financial statements as required in the NIH Grants Policy Statement.

For funded applications, the Program 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.

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)
Phone: 301-402-7469 or 866-504-9552 (Toll Free)

Web ticketing system: https://public.era.nih.gov/commonshelp
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 Center Phone: 800-518-4726

Web ticketing system: https://grants-portal.psc.gov/ContactUs.aspx
Email: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone 301-710-0267
TTY 301-451-5936
Email: GrantsInfo@nih.gov

Linda Brady, Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 301-443-3563
Email: lbrady@mail.nih.gov

John Hsiao, M.D.
National Institute on Aging (NIA)
Telephone: 301-496-9350
Email: jhsiao@mail.nih.gov

John A. Matochik, Ph.D.
National Institute of Alcohol Abuse and Alcoholism (NIAAA)
Telephone: 301-451-7319
Email: jmatochi@mail.nih.gov

Steven Grant, Ph.D.
National Institute on Drug Abuse (NIDA)
Telephone: 301-443-4877
Email: sgrant@mail.nih.gov

Eileen Bradley
Center for Scientific Review (CSR)
Telephone: 301-435-1179
Email: bradleye@mail.nih.gov

Rebecca Claycamp
National Institute of Mental Health (NIMH)
Telephone: 301-443-2811
Email: rclaycam@mail.nih.gov

Jessi Perez
National Institute on Aging (NIA)
Telephone: 301-402-7739
Email: PerezJ2@mail.nih.gov

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

Yinka Abu
National Institute on Drug Abuse (NIDA)
Telephone: 301-595-0572
Email: abuy@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.