NIH’s new Application Submission System & Interface for Submission Tracking (ASSIST) is available for the electronic preparation and submission of multi-project applications through Grants.gov to NIH. Applications to this FOA must be submitted electronically using ASSIST or an institutional system-to-system solution; paper applications will not be accepted.

It is critical that applicants follow the Multi-Project (M) 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

In 2016, NINDS organized a conference on Alzheimer's Disease Related Dementias (ADRDs) which focused on frontotemporal degeneration (FTD), Lewy body dementias (LBD) (including dementia with Lewy bodies (DLB)), Parkinson disease dementia (PDD), vascular cognitive impairment and dementia (VCID), mixed dementias including the associated diagnostic challenges of multiple etiology dementias (MED), and issues related to health disparities. The conference complemented the National Institute on Aging's "Alzheimer's Disease Research Summit 2015: Path to Treatment and Prevention." Both conferences responded to the National Alzheimer's Project Act that was signed into law in January 2011. The objective of the ADRD conference was to contribute to the efforts directed at preventing and effectively treating Alzheimer's disease, including Alzheimer's disease-related dementias, by 2025. The Alzheimer's Disease-Related Dementias Summit solicited input from internationally recognized experts to develop prioritized recommendations to guide scientific research in the next 5 to 10 years. This FOA addresses the following 2016 ADRD milestones: 1) Multiple etiology Dementias - focus area 1, milestone 4 centered on the development of diagnostic biomarkers for multi-etiology dementias; 2) Lewy Body Dementia - focus area 3, milestone 5 centered on the development and validation of diagnostic, prognostic and progression biomarkers; and 3) Frontotemporal Lobar Degeneration focus area 2, milestone 2 centered on the development of FTD biomarkers for diagnosis and disease progression.

Tremendous potential exists for the application of PET imaging for diagnosis and disease progression monitoring in natural history studies and clinical trials of ADRD disorders, but relatively few radioligands are currently available for functional imaging of targets and pathophysiological processes implicated in these brain disorders. Additional challenges exist in identifying PET ligands that provide specificity and selectivity for proteinopathies (tau, synuclein, FUS, TDP43) associated with ADRD disorders. Hence increasing the availability of PET radiotracers will aid in: a) understanding the abnormal biological processes that underlie ADRD 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.

The purpose of this Funding Opportunity Announcement (FOA) is to support a multi-center, interdisciplinary approach that uses innovative, cutting-edge technologies to identify and validate PET radioligands for ADRD pathways, proteinopathies and pathological processes such as, but not limited to synapse loss or neuroinflammatory responses associated with the human biology of ADRDs. This multi-center, interdisciplinary approach will be established through a Center without Walls, which will incorporate key scientific expertise in research projects and cores, to drive the development of PET radioligands that will facilitate improvements in clinical diagnosis and provide key biomarker tools for patient stratification, target engagement and/or disease progression for ADRD clinical trial design.

Successful development of ADRD PET ligands will be dependent on the availability of well characterized brain tissue, where the post mortem diagnosis, immunohistological characterization of protein load in the brain region to be used and associated clinical and genetic data will be key criteria for brain tissue selection. Investigators applying to this FOA are encouraged to incorporate collaborations with investigators overseeing brain bank resources in their research plan. Ideally, material transfer agreements should be in place to access tissue resources prior to application submission.

Utilization of existing resources and clinical infrastructure for ADRD research, where available and appropriate for the study are required to accelerate this discovery effort. These resources and infrastructure may include but are not limited to the NIH funded natural history studies of Frontotemporal Lobar Degeneration such as the Longitudinal Evaluation of Familial Frontotemporal Dementia (LEFFTDS) the Advancing Research and Treatment for Frontotemporal Lobar Degeneration Consortium (AFTFL) cohorts as well as Parkinsonisms, and Lewy Body Dementia cohorts collected under the NINDS Parkinson's Disease Biomarkers Program (PDBP).

ADRD Proteinopathy Consortium

It is anticipated that advances in structural characterization of ADRD proteinopathies will help to inform PET ligand development for these diseases. To coordinate these efforts a Proteinopathy Consortium will be established by NINDS that includes investigators funded under this FOA and the FOA for Structural Biology of ADRDs Proteinopathies (RFA-NS-18-015).

The overall outcome of the ADRD Proteinopathy Consortium will be a coordinated discovery effort and validation approach to identify protein species and PET ligands relevant to ADRD pathophysiology. An external liaison committee will be identified by the consortium and will be charged with providing expert knowledge support for technical advances in screening and development of PET radioligands. A face to face meeting will be held annually to integrate structural biology efforts with PET radioligand development for ADRDs.

Center without Walls Program:

• It is anticipated that an interdisciplinary research approach will enable Centers without Walls to incorporate expertise from multiple disciplines such as structural biology, biochemistry, medicinal chemistry, ADRD model systems, and first-in-human testing of new PET ligands.
• Center without Walls applications are expected to emphasize novel ideas and approaches, as well as use of state-of-the-art technologies and a team-based approach to achieve stated goals.
• Synergy must be evident among Center research projects and cores, such that successful completion of the aims could not be accomplished without the Center structure.
• Research projects and cores must coordinate efforts, such that data from projects and cores inform each other, as well as the overall direction of the Center. A minimum of two research projects are required. Each research project will focus on the in vitro and in vivo screening of PET ligands selective for a specific proteinopathy, process or pathway related to ADRD pathogenesis.
• Proteinopathies of interest include but are not limited to tau, FUS, TDP43, and synuclein, while pathophysiological processes of interest include but are not limited to neuroinflammation and synaptic loss. Tau ligands must have specificity and selectivity for ADRDs.
• A Medicinal Chemistry core is required and should provide access to technologies and support the development of reagents required by one or more research projects. The Medicinal Chemistry core will provide lead compound identification/development and syntheses of chemicals with suitable binding affinity, biodistribution, pharmacokinetics, and physiochemical properties allowing radiochemical synthesis. The Medicinal Chemistry core will identify any ligand associated toxicology and submit exploratory Investigational New Drug (IND) applications or IND applications required for first-in-human studies. The Medicinal Chemistry core will provide radiochemical synthesis of new ligands if appropriate.
• An administrative core is required and should provide overall coordination and support for Center without Walls activities.
• A clinical core to support first-in-human clinical studies will be required to test and validate the specificity and selectivity of the radioligands developed. The clinical core should provide an infrastructure that supports rapid access to patient populations relevant to the radioligand under development. The clinical core should also enable pilot human imaging studies with normal controls and pharmacological challenges with analyses of radiometabolites.
• Collaboration with other institutional or consortium efforts in ADRD research is required.
• An external scientific liaison committee will be identified in collaboration with NIH staff, within six months of release of the first year notice of grant award.
• It is anticipated that research in year 1 will focus primarily on the screening of existing compound libraries against ADRD tissue, while research in years 2 to 5 will also include medicinal chemistry efforts around new compound development and first-in-human radioligand testing.

Center without Walls Leadership:

The Center without Walls will be led by a nationally recognized neuroscientist with clinical and/or basic science expertise and active, R01-equivalent, independent funding and excellent scientific productivity. The expertise of the Center without Walls Director may be in areas outside of PET ligand development, if relevant skills can be readily applied to achievement of Center goals. Leadership of the Center without Walls will require coordination with existing government and non-government efforts in ADRD research, as well as the utilization of existing resources and infrastructure to advance the validation of tools and mechanisms developed by the Center. Success of the Center without Walls will depend upon strong communication, coordination and integration across its components and external collaborations.

Milestone Plans:

Center without Walls projects and medicinal chemistry and clinical cores should be supported by milestone plans. The milestone plans should include stringent go/no go criteria for advancing a radioligand through first-in-human studies and a timeline for transition from radioligand development to first-in-human studies. The milestone plans for projects and cores will be used to determine if the development of a ligand will progress or be terminated thereby enabling flexibility in the program to achieve the goals of the overall Center without Walls which should include advancement of PET ligands to first-in-human studies.

The following activities are not allowed under this Center Program, and applications proposing these will be considered non-responsive and will not be reviewed:

• Projects or Cores that support interventional clinical trials.
• Natural history studies
• Animal model development

Applicants are strongly encouraged to consult with NINDS Scientific/Research Staff at the beginning of the planning stage of their application (see Agency contacts, Section VIII).

Projects involving partnerships with industry, small businesses or non-government organizations are encouraged under this FOA. The policy of the NIH is that the results and accomplishments of the activities that it funds and supports should be made available to the public.

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

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

Higher Education Institutions

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

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

o Hispanic-serving Institutions

o Historically Black Colleges and Universities (HBCUs)

o Tribally Controlled Colleges and Universities (TCCUs)

o Alaska Native and Native Hawaiian Serving Institutions

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

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

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations

Considerations for inclusion of Foreign Components under this FOA.

Foreign components of the application must contribute unique scientific expertise, specialized patient cohorts, technologies and/or resources to the development of PET ligands for ADRD research.

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not 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.

The Center without Walls Director (PD/PI) should be an established leader with expertise in clinical and/or basic scientific research and a history of successful funding and proven expertise in the stewardship of large-scale research programs. Center without Walls Directors must serve as a Core Lead or Project Lead in the application. Other qualifying factors include current research productivity, active funding (NIH R01-equivalent or greater) and the capacity for visionary leadership of an interdisciplinary team. Expertise in areas beyond radioligand development is encouraged if the Director's skills can be applied in novel ways that will stimulate new approaches and the application of new technologies for ADRD radioligand development.

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

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

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

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

A button to access the online ASSIST system is available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

Most applicants will use NIH’s ASSIST system to prepare and submit applications through Grants.gov to NIH. Applications prepared and submitted using applicant systems capable of submitting electronic multi-project applications to Grants.gov will also be accepted.

It is critical that applicants follow the Multi-Project (M) Instructions in the SF424 (R&R) Application Guide, except where instructed in this funding opportunity announcement to do otherwise and where instructions in the Application Guide are directly related to the Grants.gov downloadable forms currently used with most NIH opportunities. 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:

Margaret Sutherland, PhD,
Division of Extramural Research, Neurodegenerative Program Cluster
Telephone: 301-496-5680
Fax: 301-480-1080
Email: [email protected]

Available Component Types	Research Strategy/Program Plan Page Limits
Overall	12
Admin Core	6
Core (use for medicinal chemistry and clinical cores)	6
Project (use for research projects)	12

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

The following section supplements the instructions found in the SF424 (R&R) Application Guide, and should be used for preparing a multi-component application.

Revision applications must include an Overall component and the components that are affected by the revision. Therefore, the component requirements listed below may not apply to the revision application.

The application should consist of the following components:

• Overall: required
• Administrative Core: required
• Medicinal Chemistry Core: required
• Clinical Core: required
• Research Projects: minimum of 2 required

When preparing your application in ASSIST, use Component Type Overall .

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

Complete entire form.

Note: Human Embryonic Stem Cell lines from other components should be repeated in cell line table in Overall component.

Follow standard instructions.

Other Attachments: The following information must be included. The filename for each attachment is indicated below; filenames will be used to bookmark the attachments in the application image.

Center Organizational Structure: a diagram demonstrating interactions among Center without Walls components and external collaborations if appropriate.

Enter primary site only.

A summary of Project/Performance Sites in the Overall section of the assembled application image in eRA Commons compiled from data collected in the other components will be generated upon submission.

Include only the Project Director/Principal Investigator (PD/PI) and any multi-PDs/PIs (if applicable to this FOA) for the entire application.

A summary of Senior/Key Persons followed by their Biographical Sketches in the Overall section of the assembled application image in eRA Commons will be generated upon submission.

The only budget information included in the Overall component is the Estimated Project Funding section of the SF424 (R&R) Cover.

A budget summary in the Overall section of the assembled application image in eRA Commons compiled from detailed budget data collected in the other components will be generated upon submission.

Introduction to Application: For Resubmission and Revision applications, an Introduction to Application is required in the Overall component.

Specific Aims:

Describe the overall aims of the proposed Center without Walls.

Research Strategy: The Overall section states the vision and rationale for the proposed Center without Walls, and provides an overview of integration and synergy of center activities. The Research Strategy should be organized into sections that address Significance, Innovation and Approach.

Significance: Provide a vision statement for the Center without Walls, including expected contributions by the Center, to discovery of new and existing radioligands with specificity and selectivity for ADRDs and testing of these ligands in first-in-human studies. Include the overall Center without Walls program objectives and related implementation plan for the proposed award period.

Innovation: Describe how novel approaches, technologies to be applied, investigator expertise, and collaborative activities will advance the goals of the Center without Walls program, including utilization of existing resources and infrastructure that will support the development of ADRD relevant radioligands.

Approach: Describe the general research framework of the Center. Discuss the proposed research program, highlighting its central theme. Describe the synergy among the Center components, especially the scientific and collaborative approaches that will ensure integration and synergy of Center research and activities. Detailed descriptions of preliminary data should be included within the relevant Research Project and Research Core sections, not in the Overview. For foreign components, included in the application, describe how these components present special opportunities for furthering research advancements through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and are not readily available in the United States (U.S.) or augment existing U.S. resources. Provide evidence that supports the feasibility for the formation and successful implementation of a Center without Walls that encompasses cutting edge technologies, novel approaches and the utilization of existing resources to develop radioligands relevant to ADRDs that address key proteinopathies, synaptic health and neuroinflammatory and other relevant pathogenic processes.

Letters of Support:

Institutional Commitment (required): Include a letter from a high-level institution official(s) (Dean of the School of Medicine, Vice President for Research) to confirm institutional commitment to the Center without Walls program. The letter should provide details on how institutional commitment will be established, examples of how the institution maintains and promotes scientific excellence in basic and clinical research, and how the Center without Walls research effort will be prioritized within the institution (relative to other NIH and non-NIH funded programs). Examples of institutional commitment may include, but are not limited to: provision of discretionary resources to the Center without Walls Director, funding for pilot projects, support for recruitment of scientific talent and career enhancement activities, access to institutional infrastructure, assignment of specialized research space, meeting support/space for the bi-annual meetings, and/or other means of support.

Collaboration with other institutional or consortium efforts in ADRD research (required): The letter(s) must describe collaborative efforts and/or opportunities with other institutional programs or consortium efforts in ADRDs. For example, opportunities may exist for collaboration with the NINDS Parkinson's Disease Biomarkers Program (PDBP) which currently supports cohort studies in Parkinsonisms including Progressive Supranuclear Palsy (PSP) and Lewy body dementia. NINDS, NIA and the National Center for Accelerating Translational Science (NCATS) support Frontotemporal degeneration (FTLD) natural history studies including the Longitudinal Evaluation of Familial FrontoTemporal Dementia Subjects (LEFFTDS) and Advanced Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) where collaborative opportunities may exist for both sporadic and familial forms of FTLD. The National Institute of Aging (NIA) funded Alzheimer's Disease Centers collect data on individuals with Alzheimer's Disease and related dementias and this data is available through the National Alzheimer's Coordinating Center (NACC). Support for unique foreign collaborations is allowed in this FOA and an example of non-U.S. based ADRD clinical research includes the European Alzheimer's Disease Consortium (EADC), which is a network of over 50 European centers of clinical and biomedical research excellence working in the field of Alzheimer's disease and related dementias.

Collaboration with national research resources and programs if applicable: The NIH and other government and nongovernment organizations fund unique resources and programs that encourage broad data and resource sharing such as the NIH NeuroBioBANK. Collaborations with brain bank investigators are strongly encouraged through this FOA. The letter(s) should describe collaborative efforts and/or opportunities with these national research resources and programs.

Collaboration with Nongovernmental Organizations and philanthropic entities (if applicable): Nongovernmental patient advocacy organizations have common goals for improving treatment and understanding causes of ADRD. Letter(s) should detail planned or ongoing partnerships between members of the Center without Walls (Director and/or Research and Core Lead(s)) and these groups. The letter(s) should also outline, where appropriate, any additional resources that will be provided by the nongovernmental organizations and philanthropic entities

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan and Resource Sharing Plan.

Appendix:

Limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.

PHS Human Subjects and Clinical Trials Information (Overall)

When involving NIH-defined human subjects research, clinical research, and/or clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered Yes to the question Are Human Subjects Involved? on the R&R Other Project Information form, there must be at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record within the application. The study record(s) must be included in the component(s) where the work is being done, unless the same study spans multiple components. To avoid the creation of duplicate study records, a single study record with sufficient information for all involved components must be included in the Overall component when the same study spans multiple components.

Study Record: PHS Human Subjects and Clinical Trials Information

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

Delayed Onset Study

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

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

When preparing your application, use Component Type Admin Core.

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

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant’s Project
• Proposed Project Start/Ending Dates

Enter Human Embryonic Stem Cells in each relevant component.

Human Subjects: Answer only the Are Human Subjects Involved? and 'Is the Project Exempt from Federal regulations? questions.

Vertebrate Animals: Answer only the Are Vertebrate Animals Used? question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Core Lead and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.

Budget forms appropriate for the specific component will be included in the application package.

Budget for the following Center without Walls-specific activities should be included in the Administrative Core:

• Annual ADRD Proteinopathy Consortium Meeting: Include meeting room rental, audiovisual support, travel and lodging costs for the Center Director, and Project and Core Leads to attend the ADRD Proteinopathy Consortium Meeting. This consortium meeting will include investigators from the ADRD PET Radioligand CWOW and investigators supported under the FOA for structural biology of ADRDs proteinopathies (RFA-NS-16-015).
• External Liaison Committee (ELC): Include all ELC-related costs (meeting and travel) in the proposed budget. To promote efficient spending, budgeted costs for ELC member travel will be within range of local per diem rates (as per General Services Administration (GSA) guidance) and follow general NIH guidelines for travel and expense reimbursement rates.

Note the ELC committee members should not be identified until after funding decisions are made and at that time, the ELC membership should be determined in collaboration with NINDS program staff.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

Introduction to Application: For Resubmission and Revision applications, an Introduction to Application is allowed for each component.

Specific Aims:

Describe the goals and planned activities of the Administrative Core

Research Strategy: Organize the Research Strategy into sections on Significance, Innovation and Approach.

Significance: Describe how the Administrative Core will serve as the organizational foundation for research activities of the Center without Walls, as well as how the Core will effectively support Center service as a national resource for ADRD PET radioligand development. Justify the proposed interdisciplinary research strategy governance, including coordination with foreign institutions and other funding entities.

Innovation: Describe how the Administrative Core utilizes novel approaches to maximize synergy among Center without Walls investigators, and fosters relationships with the broader research and advocacy communities.

Approach: Describe the proposed activities of the Core, including but not limited to the following:

• Promote the integration and function of Center components and activities.
• Provide support for the Center Director in oversight of Center governance.
• Provide support for the Center Director in oversight of external collaborations that support Center research projects and/or cores through provision of existing resources or infrastructure.
• Provide support for the Center Director in management of Center without Walls committees and cores including but not limited to the Medicinal Chemistry and Clinical cores.
• Organize biweekly meetings of the Center Executive Steering Committee, and monthly meetings of the Clinical and Medicinal Chemistry cores.
• After funding decisions have been made, work with NINDS program staff to identify an External Liaison Committee.
• Organize timely meetings of the External Liaison Committee.
• Maintain an accounting of resource generation and related utilization, and steps taken to maximize the research utilization of these resources within and beyond the Center without Walls.
• Provide advanced notice of manuscripts and publications to the NINDS program officer; work with the NINDS Office of Communications on press releases highlighting Center accomplishments.
• Prepare and submit annual progress reports.
• Provide assurance of compliance with NIH policy requirements.

Provide a Scientific Governance Structure that includes:

Description of the general composition and function of the external and internal committees that will provide scientific governance for the Center without Walls. Committees should include (but are not limited to): 1) External Scientific Liaison Committee; 2) Executive Steering Committee made up of the Center without Walls Director, NIH program staff, and PIs for Research projects and cores and external collaborators; and 3) Clinical oversight committee

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

Generally, Resource Sharing Plans are expected, but they are not applicable for this FOA.

Appendix:

Limited items are allowed in the Appendix.Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions

PHS Human Subjects and Clinical Trials Information (Administrative Core)

When involving NIH-defined human subjects research, clinical research, and/or clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered Yes to the question Are Human Subjects Involved? on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

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

Delayed Onset Study

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

When preparing your application in ASSIST, use Component Type 'Medicinal Chemistry Core.'

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

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant's Project
• Proposed Project Start/Ending Dates

Enter Human Embryonic Stem Cells in each relevant component.

Human Subjects: Answer only the 'Are Human Subjects Involved?' and 'Is the Project Exempt from Federal regulations?' questions.

Vertebrate Animals: Answer only the 'Are Vertebrate Animals Used?' question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

List all performance sites that apply to the specific component.

• In the Project Director/Principal Investigator section of the form, use Project Role of 'Other' with Category of 'Core Lead' and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.

Budget forms appropriate for the specific component will be included in the application package.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional

entries. All other SF424 (R&R) instructions apply.

Introduction to Application: For Resubmission and Revision applications, an Introduction to Application is allowed for each component.

Specific Aims: Describe the development strategy and statistical analysis for improvements in radioligand selectivity and specificity.

Research Strategy: The Medicinal Chemistry core will provide access to technologies and support the development of reagents required by one or more research projects. The Medicinal Chemistry core will provide lead compound identification/development and syntheses of chemicals with suitable binding affinity, biodistribution, pharmacokinetics, and physiochemical properties allowing radiochemical synthesis. The Medicinal Chemistry core will identify any ligand associated toxicology and submit exploratory Investigational New Drug (IND) applications or IND applications required for first-in-human studies.

Critical considerations for lead compound identification and development:

• Feasibility based on the density and affinity of the tracer target in brain region(s) of interest in post-mortem human brain;
• Affinity, lipophilicity, and target selectivity:
• Bmax/Kd > 5 in human subjects
• Lipophilicity: logD (ideally ~ 2)
• Target selectivity in brain region of interest; appropriate for proposed context of radiotracer use
• 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;
• Lack of substrate for ABCB1 (P-glycoprotein) or ABCG2 (BCRP)
• Amenability to labeling with 11C or 18F and metabolic stability of the label (e.g., 18F label is in a metabolically stable position);
• Amenability to production: radiochemical yield (%); practical yield (MBq); specific activity;
• Specific binding: sufficient binding potential (BP) or volume of distribution (BP > 2) to assess target occupancy by drugs or to characterize CNS pathophysiology;
• If requesting funding to conduct the assays for SAR studies, including ADMET, provide a testing funnel that shows how these assays will be ordered and grouped into testing tiers.

Considerations for in vivo assessment of a PET radiotracer candidate:

• Lack of radiometabolites: within brain, or of [18F] fluoride ion in skull;
• Amenability to accurate quantification: e.g., stable total distribution volume (VT) within scan session;
• Time-activity curves for brain and plasma;
• Robust test-retest reliability: < 10% by variation;
• Compartmental modeling with arterial input function.

Provide a plan for exploratory IND or IND application submission.

Milestone Plan:

A milestone plan should include stringent quantifiable go/no go criteria for advancing a radioligand for in vitro and in vivo testing of the compound by the CWOW projects. Timelines for: 1) transition from radioligand medicinal chemistry development to in vitro and in vivo preclinical testing; 2) toxicology testing if necessary; 3) radioligand scale up and synthesis for first-in-human trials and 4) filing of exploratory INDs or INDs should be included.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

A Resource Sharing Plan is expected and should address the broad availability of the radioligand for academic and industry application in clinical studies and trials

Appendix: Limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

When involving NIH-defined human subjects research, clinical research, and/or clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered "Yes" to the question "Are Human Subjects Involved?" on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

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

Delayed Onset Study

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

When preparing your application in ASSIST, use Component Type 'Clinical Core.'

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

SF424 (R&R) Cover (Clinical Core)

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant's Project
• Proposed Project Start/Ending Dates

Enter Human Embryonic Stem Cells in each relevant component.

Human Subjects: Answer only the 'Are Human Subjects Involved?' and 'Is the Project Exempt from Federal regulations?' questions.

Vertebrate Animals: Answer only the 'Are Vertebrate Animals Used?' question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

• In the Project Director/Principal Investigator section of the form, use Project Role of 'Other' with Category of 'Project Lead' and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.

Budget forms appropriate for the specific component will be included in the application package.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

Introduction to Application: For Resubmission and Revision applications, an Introduction to Application is allowed for each component

Specific Aims: The Specific Aims section should include Aims for first in-human testing of the new ADRD radioligands in the appropriate patient population(s) allowing for analysis of specificity and selectivity.

Research Strategy: Provide a brief clinical study synopsis that includes the following:

• Planned population
• Objectives
• Study design
• Route of administration and determination of dose levels
• Safety assessments
• PK assessments
• Safety management plan (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html and http://www.ninds.nih.gov/research/clinical_research/policies/data_safety_monitoring.htm).

Milestone plan:

Include recruitment milestones for the indicated patient population and healthy controls.

It is understood that at the time of application, some of the above may be limited or even unavailable, but an effort should be made to predict first-in-human study design when possible. Since details of the study are likely to change in the course of radioligand development, the overview may not reflect/include the final details of the protocol that will be implemented. As appropriate, applicants are encouraged to make use of NIH resources for clinical research, including ICF language for broad collection and retention of samples for future studies. (http://www.ninds.nih.gov/research/clinical_research/application_process/index.htm).

Letters of Support: If more than one clinical site will be used, include a letter of support that provides a description of the clinical population available.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

A Resource Sharing Plan is expected and should address the broad availability of the radioligand for academic and industry application in clinical studies and trials, as appropriate and consistent with achieving the goals of the program.

Appendix:

Limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

When involving NIH-defined human subjects research, clinical research, and/or clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered "Yes" to the question "Are Human Subjects Involved?" on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

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

Delayed Onset Study

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

When preparing your application in ASSIST, use Component Type 'Project.'

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

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant's Project
• Proposed Project Start/Ending Dates

Enter Human Embryonic Stem Cells in each relevant component.

Human Subjects: Answer only the 'Are Human Subjects Involved?' and 'Is the Project Exempt from Federal regulations?' questions.

Vertebrate Animals: Answer only the 'Are Vertebrate Animals Used?' question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

• In the Project Director/Principal Investigator section of the form, use Project Role of 'Other' with Category of 'Project Lead' and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.

Budget forms appropriate for the specific component will be included in the application package.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

Introduction to Application: For Resubmission and Revision applications, an Introduction to Application is allowed for each component

Specific Aims: The Specific Aims section should include Aims for in vitro (human tissue) and in vivo testing and validation. Each research project should be focused on a single target for ADRD ligand development such as, but not limited to ADRD proteinopathies such as tau, alpha-synuclein, TDP43, FUS or pathological processes such as, but not limited to synapse loss or neuroinflammatory responses associated with the human biology of ADRDs.

Research Strategy: The Research Strategy section must address the entire project scope and should include the following subsections:

• Clinical Impact (Significance)
• Biological Rationale and Compound Profile (Significance)
• Testing strategy (Approach)
• Innovation
• Table of proposed activities that provides the following information: Activity (assays, PK, in vivo animal testing etc.), throughput (e.g. samples per month), source (PD/PI lab, sub awardee, BPN Contractor), advancement criteria.

Clinical Impact (Significance): Each research project will focus on one target for radioligand development. The targets may be involved in more than one ADRD disorder, so the clinical impact and rationale for target design may cross disease entities.

• Briefly describe the current state of knowledge of the etiology, clinical characteristics, and current and projected prevalence of the proposed disease indication(s).
• Discuss how the proposed project relates to therapeutics development efforts underway in academia and industry.
• Provide a Target Product Profile (TPP), using a table that summarizes the minimal/ideal profile of the final marketed product and shows the ultimate goals of the proposed tracer development effort, such as disease indication, patient population, delivery mode, imaging duration, and standards for clinical efficacy. Explain why the minimally acceptable and ideal parameters offer advantages over currently available radioligands and how they relate to other imaging compounds under development.
• Briefly comment on the feasibility of conducting clinical studies toward the goals in the TPP (e.g., availability of patients for first in-human studies).

Biological Rationale and Compound Profile (Significance): Justify the choice of target/pathway and proposed imaging strategy.

• Describe the intended biological target/pathway.
• Provide the evidence that links this target/pathway to the proposed disease indication(s).
• Present the chemical structure of the compound(s) proposed for optimization or as the development candidates.
• Describe how the compound(s) were identified. Present structure-activity relationship (SAR) data, if available.
• Provide a Tracer Profile Table that summarizes the pharmacological and ADMET activities of the compound(s) proposed for optimization or as the development candidate. Note any potential liabilities for the tracer.

Screening Strategy (Approach): Include experimental designs and justification for all studies that will be conducted by the PD/PI and associated personnel.

• Present a table that lists the in vitro and in vivo assays that will be run by the PD/PI and associated personnel. The table should include descriptive names of the assays, the assay throughput, and the proposed advancement criteria for each assay.
• Explain the rationale for the choice of assays, assay design, and advancement criteria, and clarify how these relate to the desired radioligand properties presented in the Tracer Profile.
• Show assay validation data or present plans to optimize and validate assays. Assay validation should include testing the ligand in disease and control autopsy tissue.
• For the in vivo bioactivity study required to declare a development candidate, provide details on the study design, including power analysis and associated assumptions for sample size estimation, the process for blinding and randomization, and data handling rules, such as criteria for inclusion and exclusion of data. Describe plans for data analysis and interpretation, including what effect size would be considered minimally acceptable and clinically relevant (i.e., what constitutes a go/no-go decision for advancement into clinical development).
• If requesting funding for process development, describe the strategy for adapting the synthesis for scale up to levels sufficient to run a Phase I trial.

Innovation: Explain how the project offers a novel approach to imaging the chosen target/pathways.

• If radioligands are currently available for the target, pathway, or cellular process, explain why the proposed approach would be expected to provide a benefit over current radioligands.
• Comment on the novelty of proposed approach, target, pathway, assays or models.

Milestones:

Milestone plans should be provided for Center without Walls projects, and should include stringent, quantifiable go/no go criteria for advancing a radioligand to first-in-human studies and a timeline for transition from radioligand development to first-in-human studies.

Appendix:

Limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

When involving NIH-defined human subjects research, clinical research, and/or clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered "Yes" to the question "Are Human Subjects Involved?" on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

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

Delayed Onset Study

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

See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov.

Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies) using ASSIST or other electronic submission systems. Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

This initiative is not subject to intergovernmental review.

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.

For information on how your application will be automatically assembled for review and funding consideration after submission go to: http://grants.nih.gov/grants/ElectronicReceipt/files/Electronic_Multi-project_Application_Image_Assembly.pdf.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) and component Project Leads 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.

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 (SAM). Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by the National Institute of Neurological Disorders and Stroke. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

Use of Common Data Elements in NIH-funded Research

NIH encourages the use of common data elements (CDEs) in basic, clinical, and applied research, patient registries, and other human subject research to facilitate broader and more effective use of data and advance research across studies. CDEs are data elements that have been identified and defined for use in multiple data sets across different studies. Use of CDEs can facilitate data sharing and standardization to improve data quality and enable data integration from multiple studies and sources, including electronic health records. NIH ICs have identified CDEs for many clinical domains (e.g., neurological disease), types of studies (e.g., genome-wide association studies (GWAS)), types of outcomes (e.g., patient-reported outcomes), and patient registries (e.g., the Global Rare Diseases Patient Registry and Data Repository). NIH has established a "Common Data Element (CDE) Resource Portal" (http://cde.nih.gov/) to assist investigators in identifying NIH-supported CDEs when developing protocols, case report forms, and other instruments for data collection. The Portal provides guidance about and access to NIH-supported CDE initiatives and other tools and resources for the appropriate use of CDEs and data standards in NIH-funded research. Investigators are encouraged to consult the Portal and describe in their applications any use they will make of NIH-supported CDEs in their projects.

Applicants are required to follow the instructions for post-submission materials, as described in the policy. Any instructions provided here are in addition to the instructions in the policy.

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

For this particular announcement, note the following:

• Synergy: Each U19 application will be reviewed for the contribution the scientific project or core makes to the overall composition of the Center Without Walls, as well as the synergy between the scientific projects and core(s).
• Utilization of existing infrastructure: Each U19 application will be reviewed for the utilization of existing infrastructure and resources that are required by the Center without Walls to advance ADRD PET ligand development and first in-human testing. It is anticipated that the use of existing infrastructure and resources will accelerate activities proposed within the Center without Walls while reducing or eliminating the necessity and costs associated with setting up these resources de novo.

In addition, for applications involving clinical trials:

A proposed Clinical Trial application may include study design, methods, and intervention that are not by themselves innovative but address important questions or unmet needs. Additionally, the results of the clinical trial may indicate that further clinical development of the intervention is unwarranted or lead to new avenues of scientific investigation.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the Center without Walls 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 Center without Walls 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 center that by its nature is not innovative may be essential to advance a field.

Does the Center without Walls address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? If the aims of the Center without Walls 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?

Does the proposed Center without Walls utilize existing and emerging technologies to identify and test ADRD radioligands in first-in-human studies? Does the proposed Center without Walls address the relevance of the proteinopathy, process or pathway to ADRD human biology? Is the resource development proposed relevant to the broader dementia research community? Is there strong evidence that the proposed Center without Walls will advance ADRD radioligand development through both its scientific projects and cores?

In addition, for applications involving clinical trials

Are the scientific rationale and need for a clinical trial to test the proposed hypothesis or intervention well supported by preliminary data, clinical and/or preclinical studies, or information in the literature or knowledge of biological mechanisms? For trials focusing on clinical or public health endpoints, is this clinical trial necessary for testing the safety, efficacy or effectiveness of an intervention that could lead to a change in clinical practice, community behaviors or health care policy? For trials focusing on mechanistic, behavioral, physiological, biochemical, or other biomedical endpoints, is this trial needed to advance scientific understanding?

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the Center without Walls? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the Center without Walls 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 Center without Walls?

Reviewers will consider the following during evaluation of the Center without Walls Director:

Will the Center without Walls Director provide visionary scientific leadership for the Center? Does the Director have appropriate leadership experience, including leadership of a large-scale research program, which predicts success of the Center? Is the Director an established leader and innovator with a history of successful funding, as well as currently active funding? Has the Director made an appropriate time commitment to the Center, including leadership of a project and/or core? If the Director's primary area of expertise is in an area other than radioligand development, is it clear that the Director's skills can be applied in novel ways to the advancement and first in-human testing of new ADRD radioligands?

In addition, for applications involving clinical trial

With regard to the proposed leadership for the project, do the PD/PI(s) and key personnel have the expertise, experience, and ability to organize, manage and implement the proposed clinical trial and meet milestones and timelines? Do they have appropriate expertise in study coordination, data management and statistics? For a multicenter trial, is the organizational structure appropriate and does the application identify a core of potential center investigators and staffing for a coordinating center?

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?

During evaluation of the proposed Center without Walls applications, reviewers will consider the level of innovation specifically related to state-of-the-art radioligand development, including the following: Does the application outline novel approaches to advancing the stated goals of the proposed Center without Walls, i.e., will the proposed research advance discovery and in-human testing of radioligands for ADRD disorders? Does the Center without Walls application include the utilization of existing resources and infrastructure that will support the development of ADRD relevant radioligands?

In addition, for applications involving clinical trials

Does the design/research plan include innovative elements, as appropriate, that enhance its sensitivity, potential for information or potential to advance scientific knowledge or clinical practice?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the Center without Walls? Have investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasiblity and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

If the Center without Walls 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 individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed? Does the Center without Walls support the need for a center mechanism by demonstrating the synergy across projects and cores? Does the Center without Walls utilize existing resources and infrastructure to accelerate the discovery and validation processes associated with PET ligand development?

In addition, for applications involving clinical trials

Does the application adequately address the following, if applicable

Study Design

Is the study design justified and appropriate to address primary and secondary outcome variable(s)/endpoints that will be clear, informative and relevant to the hypothesis being tested? Is the scientific rationale/premise of the study based on previously well-designed preclinical and/or clinical research? Given the methods used to assign participants and deliver interventions, is the study design adequately powered to answer the research question(s), test the proposed hypothesis/hypotheses, and provide interpretable results? Is the trial appropriately designed to conduct the research efficiently? Are the study populations (size, gender, age, demographic group), proposed intervention arms/dose, and duration of the trial, appropriate and well justified?

Are potential ethical issues adequately addressed? Is the process for obtaining informed consent or assent appropriate? Is the eligible population available? Are the plans for recruitment outreach, enrollment, retention, handling dropouts, missed visits, and losses to follow-up appropriate to ensure robust data collection? Are the planned recruitment timelines feasible and is the plan to monitor accrual adequate? Has the need for randomization (or not), masking (if appropriate), controls, and inclusion/exclusion criteria been addressed? Are differences addressed, if applicable, in the intervention effect due to sex/gender and race/ethnicity?

Are the plans to standardize, assure quality of, and monitor adherence to, the trial protocol and data collection or distribution guidelines appropriate? Is there a plan to obtain required study agent(s)? Does the application propose to use existing available resources, as applicable?

Data Management and Statistical Analysis

Are planned analyses and statistical approach appropriate for the proposed study design and methods used to assign participants and deliver interventions? Are the procedures for data management and quality control of data adequate at clinical site(s) or at center laboratories, as applicable? Have the methods for standardization of procedures for data management to assess the effect of the intervention and quality control been addressed? Is there a plan to complete data analysis within the proposed period of the award?

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?

Are there appropriate plans for effective communication and collaboration to support the Center without Walls function and goal? Interactions supporting collaborative research should be evident among the components of the Center without Walls and through its interactions with ADRD resources, ongoing NIH-funded ADRD clinical studies and non-government activities (if appropriate).

In addition, for applications involving clinical trials

If proposed, are the administrative, data coordinating, enrollment and laboratory/testing centers, appropriate for the trial proposed?

Does the application adequately address the capability and ability to conduct the trial at the proposed site(s) or centers? Are the plans to add or drop enrollment centers, as needed, appropriate?

If international site(s) is/are proposed, does the application adequately address the complexity of executing the clinical trial?

If multi-sites/centers, is there evidence of the ability of the individual site or center to: (1) enroll the proposed numbers; (2) adhere to the protocol; (3) collect and transmit data in an accurate and timely fashion; and, (4) operate within the proposed organizational structure?

Each core will receive a single numerical score based on the following review criteria:

Review Criteria for Administrative Core

Is there a clear, detailed leadership plan for managing the Center without Wall's research and administration, ensuring appropriate prioritization of research, needed course corrections and problem identification and resolution, and effective sharing of resources, that conveys a high likelihood of effective, productive management of the Center Without Walls as a whole?

Are the core personnel qualified and experienced in the administration of a large, multi-component research program?

Are there an organizational structure and charter that will facilitate coordination, integration and timely evaluation of activities and progress?

Are there internal and external procedures for monitoring and evaluating the proposed research projects and core facilities/resources? Are there appropriate plans for management of data, animal models and other resources?

Are there plans for the utilization, as appropriate, of current NIH-funded resources?

Does the approach for the Administrative Core include a system for tracking resource generation and related utilization, as well as the identification of what steps are taken to maximize the research utilization of these resources within and beyond the Center without Walls?

Review Criteria for Medicinal Chemistry Core:

Is the proposed resource core well matched to the needs of the overall program? Does it provide essential facilities or services for one or more research projects?

What is the overall quality of the proposed core services? Are adequate quality control processes proposed for the facilities or services provided by the Core (including procedures and techniques)? What are the criteria for prioritization and usage of Core products and/or services?

Are the qualifications, experience, and commitment of the leader(s) of the Core and other key personnel adequate and appropriate for providing the proposed facilities or services?

Will the proposed Core provide cost effective services to the Program?

Is the environment for the Core adequate to support the program as proposed?

Does the milestone plan provide appropriate go/no go criteria for transition of new compounds to research projects for in vitro and in vivo testing? Does the milestone plan include stringent criteria for toxicology testing if applicable?

In years 2 through 5, is the timeline provided appropriate for transitioning compounds from the medicinal chemistry core to the research projects? Is the timeline for exploratory IND or IND filing appropriate for achieving a first in-human trial within the five-year timeline? Is the timeline for scale-up and synthesis of the radioligand for first in-human testing appropriate to achieve the overall goals of the study?

Does the approach include a plan to address feasibility based on the density and affinity of the tracer target in the brain region(s) of interest in post-mortem human brain and is the plan appropriate to achieve the goals of the study? Do milestones address quantitative go/no go criteria for lead compound development including analysis of affinity, lipophilicity, assessment of blood-brain barrier penetrance, radiolabeling, radiochemical production and assessment of ligand related toxicities?

Do milestones address quantitative go/no go criteria for the in vivo assessment of radiometabolities, time-activity curves for brain and plasma, and robust test-retest reliability?

Are the plan and timeline for exploratory IND or IND application submission appropriate?

Review Criteria for the Clinical Core

Are the scientific rationale and need for a clinical study to test the proposed radioligand well supported by preliminary data, clinical and/or preclinical studies, or information in the literature or knowledge of biological mechanisms?

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

In addition, for applications proposing clinical studies: With regard to the proposed leadership for the core, do the PD/PI(s) and key personnel have the expertise, experience, and ability to organize, manage and implement the proposed clinical study and meet milestones and timelines? Do they have appropriate expertise in study coordination, data management and statistics?

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?

In addition, for applications proposing clinical studies: Does the design/research plan include innovative elements, as appropriate, that enhance its sensitivity, potential for information or potential to advance scientific knowledge or clinical practice?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the core? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility, and will particularly risky aspects be managed?

Does the clinical study synopsis include a description of the target population, study design, route of administration and determination of dose levels, and PK assessments?

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 individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?

In addition, for applications involving clinical trials

Does the application adequately address the following, if applicable

Study Design

Is the study design justified and appropriate to address primary and secondary outcome variable(s)/endpoints that will be clear, informative and relevant to the hypothesis being tested? Is the scientific rationale/premise of the study based on previously well-designed preclinical and/or clinical research? Given the methods used to assign participants and deliver interventions, is the study design adequately powered to answer the research question(s), test the proposed hypothesis/hypotheses, and provide interpretable results? Is the trial appropriately designed to conduct the research efficiently? Are the study populations (size, gender, age, demographic group), proposed intervention arms/dose, and duration of the trial, appropriate and well justified?

Are potential ethical issues adequately addressed? Is the process for obtaining informed consent or assent appropriate? Is the eligible population available? Are the plans for recruitment outreach, enrollment, retention, handling dropouts, missed visits, and losses to follow-up appropriate to ensure robust data collection? Are the planned recruitment timelines feasible and is the plan to monitor accrual adequate? Has the need for randomization (or not), masking (if appropriate), controls, and inclusion/exclusion criteria been addressed? Are differences addressed, if applicable, in the intervention effect due to sex/gender and race/ethnicity?

Are the plans to standardize, assure quality of, and monitor adherence to, the trial protocol and data collection or distribution guidelines appropriate? Is there a plan to obtain required study agent(s)? Does the application propose to use existing available resources, as applicable?

Data Management and Statistical Analysis

Are planned analyses and statistical approach appropriate for the proposed study design and methods used to assign participants and deliver interventions? Are the procedures for data management and quality control of data adequate at clinical site(s) or at center laboratories, as applicable? Have the methods for standardization of procedures for data management to assess the effect of the intervention and quality control been addressed? Is there a plan to complete data analysis within the proposed period of the award?

Scored Review Criteria for Research Projects

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for each research project to exert a sustained and powerful influence on the identification and optimization of radioligands that can move forward for first-in-human testing based on 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? Is the prior research that serves as the key support for the proposed project rigorous? 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?

How will the project contribute to the overall success of the Center without Walls? Will the proposed research result in major rather than incremental advances in discovery and contribute PET ligands that can move to first in-human testing in relevant ADRD disorders?

Is there a compelling justification including rigorously obtained evidence for the involvement of the underlying target/pathway in disease and is there evidence to support the need for development of a radiotracer for the target or cellular process, for the proposed tracer's intended use(s), and types of questions that it would enable to be addressed?

Is a target product profile (TPP) provided and does it justify why the minimally acceptable and ideal parameters offer advantages over currently available radioligands and how they relate to other imaging compounds under development?

Does the tracer profile table (TPT) summarize the pharmacological and ADMET activities of the compound (s) proposed for optimization or as a development candidate? Are potential liabilities for the tracer identified?

Investigator(s)

Are the project lead(s) collaborators, and other researchers well suited to the project? If Early Stage Investigators or those in the early stages of independent careers are identified as key personnel, 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 project lead have a productive record of bringing novel and significant projects to fruition as an independent principal investigator? Is sufficient investigator effort dedicated to the research project and Center activities?

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?

Does the project challenge existing paradigms, address an innovative hypothesis or critical barrier to progress in the field? Is the work proposed appropriate to the expertise of the PD/PI and other researchers?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the Center without Walls? Have investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and address risk management? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

Does the research project show evidence of rigor in terms of rationale, preliminary data, experimental design and strategies to minimize bias?

Are the intended uses of the tracer and examples of questions that the tracer will enable appropriate for current challenges in ADRD clinical studies? Are the in vitro and in vivo assays proposed appropriate for the stage of compound(s) development, and does the choice of assays, assay design, and advancement criteria clarify how these relate to the desired radioligand properties presented in the Tracer Profile Table?

Do the assay validation data support continued development of the radioligand and are the plans to optimize and validate assays in both disease and control autopsy tissue appropriate?

Does the in vivo study design include power analysis, associated assumptions for sample size estimation, a process for blinding and randomization and data handling and are they appropriate and sufficient to assess the compound's potential use?

If process development is required is the strategy for scale up appropriate and sufficient to run a first-in-human trial?

In the milestone plan are there quantitative go/no go criteria for advancement of the compound(s) into clinical development?

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 Center without Walls 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.

Study Timeline

Specific to applications involving clinical trials:

Is the study timeline described in detail, taking into account start-up activities, the anticipated rate of enrollment, and planned follow-up assessment? Is the projected timeline feasible and well justified? Does the project incorporate efficiencies and utilize existing resources (e.g., CTSAs, practice-based research networks, electronic medical records, administrative database, or patient registries) to increase the efficiency of participant enrollment and data collection, as appropriate?

Are potential challenges and corresponding solutions discussed (e.g., strategies that can be implemented in the event of enrollment shortfalls)?

For research that involves human subjects but does not involve one of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

When the proposed Center without Walls 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 individuals of all ages (including children and older adults) to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

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

For Resubmissions, the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project.

Not Applicable

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

As applicable for the Center without Walls 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.

Not Applicable

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

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

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

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

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s), convened by NINDS 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.

Appeals of initial peer review will not be accepted for applications submitted in response to this FOA.

Applications will be assigned to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the National Advisory Neurological Disorders and Stroke 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.

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

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

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

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

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

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

Individual awards are based on the application submitted to, and as approved by, the NIH and are subject to the IC-specific terms and conditions identified in the NoA.

ClinicalTrials.gov: If an award provides for one or more clinical trials. By law (Title VIII, Section 801 of Public Law 110-85), the "responsible party" must register and submit results information for certain applicable clinical trials on the ClinicalTrials.gov Protocol Registration and Results System Information Website (https://register.clinicaltrials.gov). NIH expects registration of all trials whether required under the law or not. For more information, see http://grants.nih.gov/ClinicalTrials_fdaaa/

Institutional Review Board or Independent Ethics Committee Approval: Grantee institutions must ensure that the application as well as all protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the awardee must provide NIH copies of documents related to all major changes in the status of ongoing protocols. Data and Safety Monitoring Requirements: The NIH policy for data and safety monitoring requires oversight and monitoring of all NIH-conducted or -supported human biomedical and behavioral intervention studies (clinical trials) to ensure the safety of participants and the validity and integrity of the data. Further information concerning these requirements is found at http://grants.nih.gov/grants/policy/hs/data_safety.htm and in the application instructions (SF424 (R&R) and PHS 398).

Investigational New Drug or Investigational Device Exemption Requirements: Consistent with federal regulations, clinical research projects involving the use of investigational therapeutics, vaccines, or other medical interventions (including licensed products and devices for a purpose other than that for which they were licensed) in humans under a research protocol must be performed under a Food and Drug Administration (FDA) investigational new drug (IND) or investigational device exemption (IDE).

Awardee-selected projects that involve {clinical trials or studies involving greater than minimal risk to human subjects} require prior approval by NIH prior to initiation.

• The awardee institution will provide NIH with written study protocols that address risks and protections for human subjects in accordance with NIH s Instructions for Preparing the Human Subjects Section of the Research Plan.
• The awardee institution will provide NIH with specific plans for data and safety monitoring, and will notify the IRB and NIH of serious adverse events and unanticipated problems, consistent with NIH DSMP policies.

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

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research.

For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see http://www.hhs.gov/ocr/civilrights/resources/laws/revisedlep.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and http://www.hhs.gov/ocr/civilrights/understanding/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at http://www.hhs.gov/ocr/office/about/rgn-hqaddresses.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 Federal awarding agency review of risk posed by applicants. This provision will apply to all NIH grants and cooperative agreements except fellowships.

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Part 75, and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

The PD(s)/PI(s) will have the primary responsibility for:

• Determining experimental approaches, designing protocols, setting project milestones and conducting experiments;
• Adhere to existing Center without Walls study policies regarding data and radioligand sharing and other policies that might be established during the course of this activity, as appropriate and consistent with achieving the goals of the program;
• Report to NINDS Scientific Program staff regarding timeline and milestone achievement during the course of the project, as delineated in the terms and conditions of award;
• Submit annual progress reports during the funding period, in a format as agreed upon by NINDS program staff;
• Accept and implement any other common guidelines and procedures developed for the Center without Walls program and approved by NINDS program staff;
• Attend in-person Proteinopathy Consortium meeting to be held annually and organized in collaboration with NINDS program staff where PD(s)/PI(s) will present up to date findings (including unpublished results) on ongoing projects. The cost of these meetings will be covered under the current funding for this application.
• Awardees are expected to make new information and materials known to the research community not only in the annual Proteinopathy Consortium meetings but also in a timely manner through publications, web announcements, reports to NINDS program staff, and other mechanisms.
• Participate on PET ligand Center Without Walls executive steering committee
• Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.

Publications:

• The PD(s)/PI(s) will be responsible for the timely submission of all abstracts, manuscripts and reviews (co)authored by project investigators and supported in whole or in part under this Cooperative Agreement. The PD(s)/PI(s) and Project Leaders are requested to submit manuscripts to the NIH Project Scientists within two weeks of acceptance for publication so that an up-to-date summary of program accomplishments can be maintained. Publications and oral presentations of work conducted under this Cooperative Agreement are the responsibility of the PD(s)/PI(s) and appropriate Project Leaders and will require appropriate acknowledgement of NINDS and Tau Center without Walls support. Timely publication of major findings is required.

NIH staff has substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

• NINDS program staff will have substantial scientific/programmatic involvement during the conduct of this activity through technical assistance, advice and coordination. However, the role of NINDS Project Scientists will be to facilitate and not to direct the activities.
• NIH staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:
• NINDS program staff will have substantial scientific/programmatic involvement during the conduct of this activity through technical assistance, advice and coordination. However, the role of NINDS Project Scientists will be to facilitate and not to direct the activities.
• Contribute to the adjustment of research protocols, project milestones or approaches as warranted;
• Serve as a liaison between the awardees, the NINDS Advisory Council and the larger scientific community;
• Serve on the Proteinopathy Consortium External Liaison Group as appropriate;
• Serve on the ADRD PET ligand Executive Steering committee,
• Assist in promoting the availability of data and resources developed in the course of this project to the scientific community at large;
• Assist awardees in the development, if needed, of policies for dealing with situations that require coordinated action;
• Retain the option to recommend the withholding or reduction of support from any cooperative agreement that either substantially fails to achieve its goals according to the milestones agreed to at the time of award, fails to maintain state-of-the-art capabilities, or fails to comply with the Terms and Conditions of the award including radioligand and data sharing requirements.
• Additionally, an NINDS program official or NINDS program director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.

Areas of Joint Responsibility include:

None; all responsibilities are divided between awardees and NIH staff as described above.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

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

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

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

In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 Award Term and Conditions for Recipient Integrity and Performance Matters.

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

eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten on-time submission, and post-submission issues)

Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application processes and NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-945-7573

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: [email protected]

Margaret Sutherland, PhD
National Institute for Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-5680
Email: [email protected]

Nina Silverberg, PhD
National Institute on Aging (NIA)
Telephone: 301-496-9350
Email:[email protected]

Chief Scientific Review Branch
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-4188
Email: [email protected]

Tijuanna E. DeCoster, PhD
National Institute of Neurological Disorders and Stroke (NINDSI
Telephone: 301-496-9231
Email: [email protected]

Jennifer Edwards
National Institute on Aging (NIA)
Telephone: 301-827-6689
Email:[email protected]

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

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75.