Required Application Instructions

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

Part 1. Overview Information
Part 2. Full Text of the Announcement

Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

The National Institute of Neurological Disorders and Stroke (NINDS) is soliciting applications for a repository for biospecimen banking of human, mostly biofluid-based specimens from studies of neurological disorders.

The NINDS has established several biomarkers programs and supports individual grants in this area. In order to further support and provide infrastructure for these efforts, the NINDS has established a human biomarkers specimen collection. The NINDS biomarkers biospecimen collections currently underway or recently completed include Parkinson's Disease (PD), Huntington's Disease (HD), Traumatic Brain Injury (TBI) via the Federal Interagency Traumatic Brain Injury Research (FITBIR), and others. The Parkinson's Disease Biomarkers Program (PDBP) was established in 2012 to advance the discovery of PD diagnostic and progression biomarkers to allow better neuroprotective agent trials. The BioFIND project, sponsored by the Michael J. Fox Foundation with biobanking collaboratively supported by the NINDS, is a cross-sectional study to collect samples for discovery projects in PD biomarkers. The PREDICT-HD project, a collaborative project between NINDS and the CHDI Foundation, is a longitudinal natural history study seeking to identify the earliest clinical and biological changes in a prodromal HD patient population. FITBIR is an interagency infrastructure system that includes a data management system for the curation and sharing of data across projects as well as a biospecimen collection. All of these extant collections will become part of the new repository funded under this FOA.

Considering the considerable potential of biomarkers to provide information about disease diagnosis, progression, and treatment, it is likely that additional biomarkers efforts in these and/or other neurological disorders will follow in future years. The recipient of this award is expected to coordinate with future banking projects so that an appropriate budget can be included by those investigators in their planned project to allow appropriate banking with the repository. NINDS will work to help assure that future projects are aware of the need to include such items in their grant application budgets.

A successful application will have strengths in three major areas of emphasis: 1) Administration/Project Management, 2) Research and Resource Activities, and 3) Data Management. NINDS will use annual milestones to make go/no go funding decisions.

The administrative structure should provide leadership and program management skills to the entire project. The overall program should be designed to insure effective sharing of linked data and biosamples so that stakeholders including academic and industry scientists, research subjects, and the public will be served by the resource. As a cooperative agreement, this activity will receive extensive input from the NINDS.

The Research and Resource activity requires a team with a track record of academic excellence in the field of biomarkers, especially, an understanding of protocol harmonization, analyte standards, and quality control and assurance. The Research and Resource team must be poised to continue the collection and maintenance of neurological biomarkers data and specimens using standardized protocols and guidelines (examples include those being used by the PDBP (see "toolbox"), and those outlined in the literature, while keeping abreast of standards as they evolve. Additionally, the team should be able to nimbly suggest and adopt new standardization and quality control methods (once agreed upon in collaboration with NINDS and other stakeholders). Raw and analyzed data should be made widely available via the project website if the associated projects do not themselves host a website for this activity.

A web-based portal for this project will need to be developed and launched by the recipient of this award, within the first month after award, and updated in an ongoing way to reflect growth of the project. Inventory management, sample tracking, and publication monitoring will be essential required activities of this project. Data management and web-based activities will include creating and curating a searchable database with detailed pre-analytic quality control (QC) and protocol information on a sample by sample basis (such as site details, time between collection, shipping, freezing or other processing, needle bore sizes, centrifugation, etc). This activity will require coordination and data integration with other data management resources (such as the Parkinson's Disease Biomarkers Data Management resource, (PDBP DMR), the Federal Interagency Traumatic Brain Injury Research Informatics system (FITBIR), and the PREDICT-HD data management system, among others. The data management team must be able to smoothly interact and coordinate data sharing activities with multiple other entities including global research teams collecting or requesting samples and data.

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

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

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

Other

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

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are not allowed.

Applicant Organizations

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The letter of intent should be sent to:

Katrina Gwinn, MD
Telephone: 301-496-5745
Fax: 301-402-1501
Email: gwinnk@ninds.nih.gov

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed, with the following exceptions or additional requirements:

For this specific FOA, the Research Strategy section is limited to 30 pages.

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

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

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

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

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

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

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

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

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

Specific Aims: Provide a succinct description of how the proposed work will meet the overall scientific goals, the expected outcomes, and the impact should those goals be achieved. Goals should include:

• Providing leadership to the entire project. This requires overall project management of the research and resource goals, the ability to receive and organize previously collected biosample repositories, to dovetail with ongoing and future biomarkers projects of interest to the NINDS, strategies for inclusion of new biomarkers projects and biospecimen collections when approved by NINDS, and plans for working with a range of stakeholders including government, academic scientists, industry, data-management experts, and the lay public.
• Providing scientific and laboratory expertise. This will require the skills and flexibility to apply cutting-edge science to the development and use of biomarkers protocols, QA/QC assays, and batch effect analyses. It will require coordination of the receipt, processing, storage, and distribution of biospecimens from a variety of global projects.
• In terms of data management, the resource must be able to link clinical data with biosamples, coordinate IT efforts across projects and databases supporting biomarker banking, biomarker discovery and clinical assessments. Projects supported by this resource will include both academic and industry-based research. Data sharing and protocol standardization will play a significant role in the success of this resource. The sharing of raw and analyzed data, protocols, quality assurance, and other data generated by the research team is expected. A user-friendly, query-based website is an essential component of the overall activity.

Research Strategy: Overall, the application must address three broad categories: 1) Administrative Structure, 2) Research and Resource Plan, and 3) Data Management and Web-Based Component.

Administrative Structure:

Provide an overall description of the proposed organizational structure and project management plan. Describe the strategy for effectively carrying out each specific aim. Applicants must present an integrated plan that will be responsive to and flexible regarding the evolving needs of the scientific community. In particular, applicants should address:

• The management plan for the proposed project in the context of the overall organization of the proposed research resource.
• The administrative structure of the project, including an organizational chart, and planned meetings, proposed committees and user groups, and other activities which will involve NINDS and other stakeholders.
• How collaborations or subcontracts, if proposed, will be managed.
• Describe particular contributions and skills in neurological biomarkers research such using relevant analyte assays, QC or other sample characterization that are not described on the Biosketches.
• How the management plan will facilitate and maintain communication with clinicians submitting specimens, patient advocacy groups, biomedical researchers who request samples, and NINDS.
• Education and Training. The utility of the resource will be dependent upon high standards in biosample banking and an effective outreach program that will engage researchers across many disciplines interested in neurological biomarker research. Education and training of investigators collecting biosamples will be required to ensure standardization and high quality sample collections.
• Existing collections. Transfer, maintenance, and distribution of existing collections will be needed. For estimation purposes, it is anticipated that samples from up to 2000 unique subjects including plasma/serum, whole blood for DNA and for other purposes, PAX-gene (RNA), cerebrospinal fluid, and possibly, saliva and urine, may be transferred from the existing NINDS repository during the course of this activity. Some subjects have only a single sample type collected, others, the entire range; for estimation purposes, we expect an average of 3 sample types per subject. Extant samples include those collected for the Parkinson's Disease Biomarkers Program (PDBP), PREDICT-HD (Huntington's Disease), and Traumatic Brain Injury (FITBIR). Transfer of these collections will require coordination with the existing NINDS repository contractor (at NINDS expense via that contractor). Extant samples and their maintenance and distribution will become the responsibility of this project thereafter.
• Future collections. The NINDS anticipates that individual grants and other projects will bank biospecimens from projects approved by NINDS. It is expected that the costs for banking will be included in those grant applications planning to bank samples. Furthermore, recipient of this award is expected to work directly with potential bankers to develop budgets for biosample banking in a timely fashion prior to submission. A brief discussion regarding how this will be coordinated by the awardee should be included, with the specifics of the costs for each sample collection included in the body of the application. NINDS will advise applicants of the importance of contacting the Repository prior to their grant submission so that they can appropriately gauge the budget they need to submit in order to bank samples. Appropriate estimation of costs is the Repository's responsibility.
• All IRB-related activities must be coordinated by the awardee with the contributing Investigators/Institutions.
• Coordination of the proposed awardee's activities with those of other biobanking efforts at the awardee site, if any, must be described, including Material transfer agreements and Intellectual property.
• A Scientific Liaison committee is required to provide input to the research team regarding operational and mission related aspects of the resource. It may also participate in evaluation activities along with NINDS staff regarding repository accomplishments. The committee will be recommended by the applicant, but final approval and additional members may be recommended by the NINDS.

Research and Resource Plan: The applicant should state concisely the goals of the proposed Resource and Research activities, which consists of the following three subsections:

1. Strategies for bringing scientific expertise to bear upon the project, including protocol harmonization, analyte measures, and quality control and assurance. Describe in general terms the approach to incorporate ongoing advances in the field of biomarkers biospecimen handling, and neuroscience, into the ongoing project, in the context of other biomarkers activities. The team should plan to make all raw and analyzed data from internal repository activities, including, sample characterization and quality measures, widely available. Give any specific examples of successful creation and/or adoption of assays for biomarkers characterization, and how this expertise would contribute to the resource. The use of proprietorial markers, assays, or other materials which will generate data but which won't be shared will not be considered generally acceptable, as the overall goal is to broadly make all such data widely available.

2. Transfer and maintenance of existing NINDS Biomarkers collections. While it is expected that the cost of transfer will be borne by the existing NINDS Repository contractor, it is also expected that the awardee will take an active role in planning a successful transfer. Describe plans to maintain the current collection of the NINDS Biomarkers (currently housed at Coriell Cell Repositories). This collection contains approximately 80 thousand samples from 2000 unique subjects, including: Plasma, Whole Blood, DNA, Pax-gene tubes (RNA), saliva, urine, and cerebrospinal fluid (CSF). Note that fibroblast lines will be stored and managed separately via another related resource. Supplementary information about the current biomarkers collection can be found at http://www.coriell.org/research-services/biomarkers/coriell-partners. Transfer may include coordination of permissions from IRBs for certain collections. Applicants should include within the body of the grant application an item-based cost estimate for accepting existing samples of serum, plasma, DNA, CSF, urine, saliva, and linked clinical data.

3. Processing/Characterization, Maintenance, and Storage.
a) It is expected that newly collected samples will be submitted to the repository within 24 hours of each subject visit. Applicants must demonstrate that they are able to follow existing standard operating procedures for sample handling. Therefore, the repository must describe an ability to coordinate shipping and to receive samples to accommodate this requirement, including on weekends and holidays if necessary. Applicants should include a cost estimate for accepting, processing, storing, performing QC, and distributing different sample types (ie, whole blood, serum, plasma, spinal fluid, urine, saliva), as well as the costs of preparation and handling of DNA, cellular RNA. In particular, details regarding assessment of blood contamination of CSF must be addressed.

For planning purposes, the following volumes are generally anticipated for an individual subject (note: not all types would be collected for all studies):
-Plasma/Serum: estimated 6 milliliters
-Whole blood (for DNA extraction): estimated 6 milliliters
-Whole blood (for other studies): estimated 6 milliliters
-PAXgene tube (for RNA): estimated 8 milliliters
-CSF: estimated 10 milliliters
-Urine: estimated 5milliliters
-Saliva: estimated at 5milliliters
(Note that each sample type may be sub-divided into smaller aliquots at sites prior to submission.)

Additional existing archival sample collections from academics or industry may be submitted to the repository if specific conditions for NINDS approval are met, upon NINDS request. If any samples are to be stored under a subcontract, they shall not be distributed nor used for research by the subcontractor without prior NINDS authorization.

b) Processing and Characterization. Propose detailed plans for preparation of sample types in the repository collection. Plans should describe how the proposed methods and processes will ensure the distribution of high-quality characterized samples to the biomedical research community for appropriate research projects. For example, describe the approach for processing DNA from whole blood samples, as well as from other possible sample sources (such as saliva, tissue). Describe processing of RNA from PAX-gene tubes. Describe quality control methods that ensure the purity and stability of analytes across multiple studies. Describe methods for characterization of newly acquired samples. Describe any sample-specific characterization, and sample-type specific quality assurance procedures planned. Describe services available for screening of known variants, ancestral informative characterization, or other approaches for genotyping sample collections. Describe planned sample tracking methods (such as bar-coding and/or SNP genotyping).

c) Maintenance and Storage. Describe plans for maintenance of the existing collection. Describe safeguards against accidental loss of the collection including, storage of duplicates at a remote site, freezer failure back-up and plan, and other contingencies. Describe safeguards to prevent temperature changes when freezers are accessed, alarm systems and procedures, and other safeguards if they exist. Lost samples may be re-collected at the expense of the awardee, depending on the circumstances, at the request of NINDS.

d) Budget planning. It is expected that the recipient of this award would use their funds from this award to pay for costs of new collections including shipping, receipt, processing, QC, storage, tracking, catalogue addition, search tools, and other data management related to samples and their associated clinical data. It is anticipated that the submitters of new collections would be expected to include funds in their grant applications to cover the costs of sample collection and clinical and other participant phenotypic characterization.

4. Distribution of Biospecimens for Biomarkers Discovery, Replication, and Validation studies.

The NINDS has established a Biospecimen Resource Acquisition Committee (BRAC) for several extant collections, which will continue to function under NINDS direction. Other resources have separate approval processes. Describe in general how requests for samples will be acknowledged, how approvals will be sought (if appropriate), and how samples will be distributed. Describe safeguards against any loss or damage to samples during shipping (to the extent possible). These plans should include both US and international recipients.

Additionally, applicants should:
Describe their Human Subjects expertise: It is likely that most samples will not be subject to Human Subjects regulations, as most will be de-identified and HIPAA compliant. However, rare collections may have Human Subjects aspects. For this reason, include proposed procedures for evaluating and maintaining adherence to Health and Human Services and NIH guidelines and regulations on informed consent and research resources, including information technology security and the implications of the Health Insurance Portability and Accountability Act (HIPAA) regulations Privacy Rule. Describe plans for the Institutional Review Board (IRB) that will review the use of materials that are considered human subjects.

Provide turn-around times for regularly performed activities including timelines for processing from sample receipt to storage, sample request approval to shipping, protocol deviation to reporting to NINDS, and other activities. Where possible, integrate timelines for these activities into project milestones.

Note the following regarding the ownership and custodianship of samples:
Once deposited, the original donor will have the right to remove samples from the repository. However, once samples have been distributed, it will not be possible to retrieve any such samples. Ideally, a single material transfer agreement (MTA) should be utilized to cover all activities of this repository (i.e., it is expected that individual MTAs will not be negotiated for individual users). NINDS has developed guidance regarding MTA that is recommended (seehttp://tto.ninds.nih.gov/mta.asp). At any point during the project, as well as at the time of project termination, the NINDS has the right to transfer all samples to a site of NINDS discretion.

Data Management and Web-Based Activities:
The applicant must describe plans for maintaining a computerized data management system for cataloguing, querying, and retrieval of sample-related information. The system must provide effective data management solutions for quality control data, order fulfillment, billing methods for cost reimbursement, shipment, and inventory tracking. Present plans for a back-up system to protect against accidental loss of valuable data. The design and development of the database should provide user-friendly accounting of the repository's holdings, and ensure data integrity, accuracy, and security. Such information should include but is not limited to: a global unique identifier, sample type, sample volume/weight/aliquot size, inventory data, and processing data, including QC for individual specimens (such as such as time between collection, shipping, freezing or other temperature changes, processing, needle bore, centrifugation, etc.)

Applicants must address their strategy to provide the following:

• A data management plan which will include solutions for tracking inventory, catalogue, and other necessary information for biomarkers researchers
• A public web-based interface to promote the goals of the NINDS biomarkers program and to provide tools such as protocols, procedures, and policy guidance
• Database views and tools to allow easy searching, identification, and requesting of biospecimens and associated data
• A plan for monitoring of publications related to use of the resource. This will allow NINDS to partially gauge the scientific impact of the biorepository activities.

Data management activities must dovetail with a variety of other data management resources in academic and industry settings. The data management capabilities must be 1) nimble in sharing inventory and catalogue data on a regular basis 2) able to receive clinical and other sample associated data 3) able to track and 4) notify submitters and requestors regarding sample status (via an electronic system). Sharing of data with NINDS Program staff and their designees is expected in real time. Dedicated staff must be available for trouble-shooting any data management aspects of the project.

Integrating with Related Projects. Flexible, problem solving approaches towards unique situations for various shareholders is essential. Present a general plan for how you will integrate with research projects and their data management approaches. There may be designated data form structure requirements for sharing data with other projects to facilitate this activity as appropriate. If none exists for certain special projects (ie, those with data generated via unique technologies), these must be created collaboratively.

Web-based Catalog. Describe plans for a Web-based electronic catalog, which must be made available for collections where such resources do not/will not exist. Note that for some biomarkers projects, a catalogue will be hosted by the awardee; in others, by the biomarker project itself via NINDS funding (such as is being done, for example, by the PDBP DMR and FITBIR). If hosted by the awardee, the catalog must outline the policies and procedures for governing the submission and requesting of samples. This should list the available samples with associated information, including detailed phenotype and molecular genotype data, links to related genetic databases, pedigree structure when relevant and available, assay results, and all quality assurance information.

Customer Service. Describe plans for customer service, including plans for a user-friendly customer service interface, such as a help-desk. This help-desk function should serve not only those with IT and data management-related concerns, but the entire spectrum of Research and Resource activities. For example, this help-desk function would provide support for the following activities: protocol clarification, QC processes and results, sample submission, sample requests/ordering, and shipping questions.

Publicizing Repository Collections. Describe plans to publicize repository collections. Efforts may include publishing articles in relevant scientific journals that describe specific repository collections or the general purpose and operation of the repository, presentations at scientific meetings to represent the scientific activities and collaborations, or other activities. The aim of the activities should be to increase the use of repository collections, to promote awareness of repository services to the scientific community, and/or to aid in recruitment of additional samples for the repository collection when appropriate. Additionally, the public website should serve as a means to educate patients with neurological diseases and the other members of the lay public regarding biomarkers advances resulting from repository activities.

Additional Application Elements:
Applicants must also address each of the following key elements:
1. Milestones. Annual milestones must be provided in the context of a study timeline. These milestones will provide clear indicators of a project's continued success or emergent difficulties. Milestones are goals that create go/no-go decision points in the project and must include clear and quantitative criteria for success. Milestones should include timely processing of sample submissions and requests, and clear communication timelines with NINDS and other stakeholders. Funding of non-competing award years will depend on milestone accomplishment as assessed by NINDS program staff.
2. Cost-Recovery program. Outline an overall cost-recovery program that provides a plan for a charge-back fee for distribution of samples. Ideally, this charge-back plan should take into consideration the importance to the NINDS of serving the community and promoting broad sharing, and therefore, should not be onerous nor provide a disincentive for use of the collection.

Letters of Support: Statements of Institutional Commitment, if appropriate, should be included in this section. In addition, a letter from the applicant should be included and titled "Procedures related to materials obtained from human subjects" that provides documentation of the following:
That the resource's offices that handle or process the samples and data for biomedical research are in compliance with the Health Insurance Portability and Accountability Act (HIPAA).
That the resource will not accept specimens for the resource's use from any human subject unless that subject or subject's representative has given signed, explicit consent.

All letters of support should be concatenated into one attachment for uploading.

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 Standard Operating Procedures, laboratory manuals, and other procedural documents are expected to be made freely available, in order to allow harmonization across studies and in order to have full transparency regarding laboratory procedures, thus limiting the risk of batch effect in Biomarkers Research findings.

Appendix: Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.
Appropriate Appendix material may include:

• Laboratory Protocols including QA/QC activities and sample aliquoting procedures.
• Screenshots of Database views if relevant to data management capabilities.
• Standard operating procedures for equipment monitoring and maintenance.
• Facility-derived training, continuing education, and certification programs for personnel.

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

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

Part I. Overview Information contains information about Key Dates. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission.

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

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

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

This initiative is not subject to intergovernmental review.

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

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

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

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

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically. 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.

Important reminders:
All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

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

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

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Does the project address an important problem or a critical barrier to progress in the field? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field? Is there convincing evidence that the proposed plan for managing the resource will stimulate and facilitate Neurological Biomarkers research efforts by optimizing access to high-quality, well-characterized biospecimens and data?

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

Additionally:
Does the research team have a track record of managing complex projects?
Does the team have a track record of collaboration and sharing?
Does the research team have experience in biomarker research, such as evaluation of batch effects, protocol development and standardization, and analyte quality control measures?
Does the scientific staff have appropriate expertise in neuroscience?
Is there confidence that the Key Personnel will stay abreast of advances in the biomarkers field, and bring cutting-edge scientific knowledge to the project?
Does the research team have experience in data management?

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? Is there evidence that new technologies and innovative approaches will be adopted when indicated in order to insure high-quality biospecimen availability for the research community? Is there evidence that innovative approaches will be taken to identifying new characterization methods for the collection?

Is there a high likelihood that the activities proposed will remain scientifically current to the greatest extent possible, given rapid advances in biospecimen science, molecular biology, and information technologies?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed?

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

Is the management plan well integrated and likely to facilitate achieving repository goals and objectives? Does the application inspire confidence regarding an ability to recognize the priorities of the neurological biomarkers scientific community?

Does the application address plans for broad sharing of protocols and standard operating procedures, and an approach for insuring that these occur?

Are appropriate plans in place for training staff and assuring continuity of activities in the case of staff turnover?

Is the plan for transfer of existing collections clear and feasible?

Are plans for characterization of newly acquired specimens robust and likely to be broadly valuable? Are plans for quality control, data collection and analysis, and diagnostic verification likely to result in distribution of high-quality, well-characterized samples to the biomedical research community?

Does the application present a plan to prevent the loss of samples and/or data, including provision of off-site storage facilities? Is there a plan for recovery or replacement should any samples be lost? Are personnel available in case of equipment failure or other mal-function at all times including nights, weekends, and holidays?

Is the proposed database likely to provide a user friendly accounting of the resource's holdings and ensure data integrity, accuracy, and security? Are plans for customer service likely to facilitate use of biospecimens by biomarkers researchers? Are plans for a web catalogue and query system presented and feasible? Is integration with other projects data management systems likely to be successful?

Does the application present a cost-recovery program that will allow sensible budgetary management of the resource, without creating a dis-incentive for use of the resource?

Is there a clear plan for public outreach and publicizing repository resources?

Does the application provide appropriate milestones which are clear, quantifiable, including specific turn-around times and communication timelines?

Is an appropriate budget estimate provided regarding costs of accepting existing sample collections and banking future samples of various types for individual researchers who choose to submit samples? Is the estimate specific enough to judge the reasonableness of the costs for these banking activities prospectively?

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?

Is there adequate server capacity to support a variety of activities including clinical data management, data query, file protocol sharing, SNP genotyping and genomics, and other data banking and management?

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

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

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

When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of children to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

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

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.

Not Applicable

Not Applicable

Not Applicable

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

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 Wide Association Studies (GWAS) /Genomic Data Sharing Plan.

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

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by the 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 (NANDS) 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.
• An ability to fully comply with the sharing policies as appropriate and consistent with achieving the goals of the program.

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

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

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

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

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

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

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

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 Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), 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 NINDS and NIH policies regarding appropriate data and biospecimen sharing and other policies that might be established during the course of this activity;
• Report to NINDS 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 biomarkers specimen banking and tracking, research and public outreach, and approved by NINDS program staff;
• Coordinate with other projects at NINDS, including sharing of data with a centralized data management resources as appropriate and consistent with achieving the goals of the program;
• Attend in-person Biomarkers projects meetings up to five times per year (ie, yearly for individual projects) and present up to date findings (including unpublished results) on ongoing activities at these meetings.
• Participate in individual project steering committee calls, an average of one per project per month, or about five a month.
• Awardees are expected to make new information and materials known to the research community in a timely manner through publications, web announcements, reports to NINDS program staff, and other mechanisms.

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 Scientist 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 support. Timely publication of major findings is required.

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.

The NINDS Project Scientist will:

• 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;
• Coordinate the efforts of the awardee with others engaged in PD research, including other awardees under this FOA and those involved in related NINDS programs;
• Serve on project committees as appropriate;
• 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 biospecimen and data sharing expectations.

Areas of Joint Responsibility include:
None.

Other Project-Related Components

Biospecimen Resource Acquisition Committee (BRAC)
The Biospecimen Resource Acquisition Committee (BRAC) will be chosen by the NINDS to evaluate requests for biospecimens based on transparent criteria for distribution towards biomarkers discovery projects. It is intended that biospecimens be available for research studies by academics and industry investigators. The awardee will insure that sample distribution approved by the BRAC will occur as fast as possible following approval.

Formation of an External Scientific Liaison Committee and ad hoc user groups. An external Scientific Committee is required to provide input regarding operational aspects of the repository. This may include recommendations about sample acquisition, biospecimen characterization, and sample preparation. The Scientific Liaison Committee may also participate in quality control by assisting project staff in review of clinical documentation and laboratory based data associated with samples before distribution of samples to the scientific community. Note that the Scientific Liaison Committee will be advisory to the Project, not to the NINDS-NIH. However, the final members of the Liaison Committee will require NINDS approval, and NINDS will reserve the option to add ad hoc and permanent members during the course of the project. The awardee will be expected to organize and bear the cost for monthly and ad hoc conference calls, and up to one in-person meeting per year. This meeting will include various stakeholders, including investigators banking samples, data-management resource leaders from related projects, NINDS staff, and the Scientific Liaison committee.

Opportunities for Partnership
Projects involving partnerships with industry, small businesses or non-government organizations are encouraged under this FOA. The policy of the NIH is to make available to the public the results and accomplishments of the activities that it funds. To ensure that research resources are made accessible to the broader biomedical community, NIH expects applicants who respond to this funding opportunity to submit a plan for: (1) sharing the research resources generated through any grants awarded and (2) addressing how they will exercise intellectual property rights, should any be generated through an award, while making such research resources available to the broader scientific community consistent with this initiative. Projects involving studies in which databases already exist or have been created via other resources may be maintained under those projects, but not funded via this program. However, it is expected that these databases will become federated under this project.

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

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

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

eRA Commons Help Desk (Questions regarding eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)
Finding Help Online: http://grants.nih.gov/support/index.html
Email: commons@od.nih.gov

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact CenterTelephone: 800-518-4726
Web ticketing system: https://grants-portal.psc.gov/ContactUs.aspx
Email: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-710-0267

Katrina Gwinn, MD
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-5745
Email: gwinnk@ninds.nih.gov

Chief, Scientific Review Branch
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9223
Email: nindsreview.nih.gov@mail.nih.gov

Tijuanna DeCoster, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9231
Email: decostert@ninds.nih.gov

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

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