Part 1. Overview Information

Key Dates

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 2. Full Text of Announcement

Section I. Funding Opportunity Description

Background

Under the 2009 American Recovery and Reinvestment Act (ARRA), the National Institute of Neurological Disorders and Stroke (NINDS) supported three consortium efforts to develop human induced pluripotent stem cell (iPSC) resources for familial forms of adult-onset neurodegenerative diseases. From this and subsequent efforts, the NINDS Repository now offers cell lines from 343 subjects, including 235 human fibroblast lines and 131 human iPSC lines from healthy control subjects, individuals with neurological disorders including Huntington's disease, Amyotrophic Lateral Sclerosis, Frontotemporal Degeneration, Spinal Muscular Atrophy, Spinal-Bulbar Muscular Atrophy, Dystonia, and Parkinson's disease. To date the NINDS Repository has distributed over 1800 fibroblast lines and over 500 iPSC lines worldwide to both academic and industry researchers.

Given the rapid advancements in technologies for both iPSC derivation and genome editing, and the continued demand for human fibroblast lines representing both rare and common forms of neurological disorders this FOA supports further advancements, expansion, and standardizations in iPSC lines and source cell resources for basic research and drug discovery efforts in neurological disorders supported by the NINDS. It is expected that the existing and new resources developed under this FOA will continue to be broadly distributed to both academic and industry researchers worldwide.

Scope

Activities required under this FOA include:

• Maintenance and distribution of current fibroblast, peripheral blood mononuclear cell (PBMC) and iPSC lines available through the NINDS Repository;
• De novo derivation, quality assessment and distribution of new iPSC lines using a standardized non-integrating protocol for derivation. Quality assessment standards should include, but are not limited to those outlined in NOT-NS-14-032;
• Establishment of master and distribution banks for iPSC lines which meet banking standards established by NINDS (see NOT-NS-14-032);
• Limited expansion, quality assessment and distribution of fibroblast lines wherein patient consents allow for banking with a repository and broad distribution of these lines;
• De novo generation, quality assessment and distribution of fibroblast lines. Quality assessment of fibroblast lines should include karyotyping at the distribution phase to ensure normal karyotypes;
• Generation and maintenance of a peripheral blood mononuclear cell source for future iPSC derivation efforts. Extensive de-identified clinical data must accompany each sample and a global unique identifier (GUID) will be used to link the clinical data with the cell resource;
• Generation, quality assessment and distribution of isogenic iPSC lines through genome editing using standardized protocols. The parent and corresponding genome-edited lines must undergo standardized quality assessments including whole genome sequencing;
• Data management including a catalog of all cell sources available through the NINDS Repository, as well as routine tracking and reporting of submissions, requests, and distribution.

A successful application will have strengths in four major areas of emphasis: 1) iPSC technology and genome editing; 2) project management; 3) resource creation, maintenance, and operation; and 4) data management. Qualifications for applicants should include academic excellence in the field of induced pluripotent stem cell derivation, quality assessment, and genomic editing.

The administrative structure should be such that it provides leadership and program management to the entire project. Because this is a cooperative agreement, extensive collaboration and management input from the NINDS will occur, and milestones will be used to make go/no go funding decisions. This overall structure is intended to ensure that stakeholders including academic and industry scientists, and research subjects will be served by the resource. The resource and research activities will also require the continued collection and maintenance of existing NINDS Repository human cell lines and data. Other disorders are likely to be added during the duration of the project. Receipt, processing, storage, and the national and international distribution of iPSC and fibroblast cell lines will be required.

Applications that propose to develop non-human cell resources are non-responsive to this funding announcement.

Due to the unique requirements of this project, applicants are strongly encouraged to consult with NINDS Scientific/Research Staff early on during the planning for an application.

Section II. Award Information

Section III. Eligibility Information

1. Eligible Applicants

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

• 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

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) 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 to register in eRA Commons. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration , but all registrations must be in place by time of submission. 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.

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.

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

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)

Section IV. Application and Submission Information

1. Requesting an Application Package

The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

Letter of Intent

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:

Christine Swanson-Fischer
National Institute of Neurological Disorders and Stroke
Telephone: 301-496-5680
Email:[email protected]?

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

Highlight, how the Research Team has appropriate expertise (without duplicating information in the biosketches) in :

• Characterization, quality control and assurance measures for iPSC and source cell resources
• Human Subjects including familiarity with HHS and NIH guidelines and regulations on informed consent and research resources as well as compliance with HIPAA
• Data Management and Web-based catalog design and support

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

If appropriate, the applicant should budget for the intake of the existing NHCDR collection.

Research Strategy

Acquisition, Characterization, Quality Control and Assurance Measures, De Novo Derivation, Genome Editing, Maintenance and Storage and Distribution for NINDS Repository human induced pluripotent stem cells (iPSCs), human peripheral blood mononuclear cells (PBMCs), and human fibroblasts.

Propose plans that describe how valuable existing and new samples from projects identified by NINDS will be supported by the Repository. Plans should address how the proposed procedures and processes will ensure standardized banking and distribution of verified, high-quality, uncontaminated samples that will advance biomedical research. Address each of the following key areas:

• Acquisition. Describe, in general terms, procedures for accessioning of biomaterials and corresponding clinical data for the development of human cell sources including from researchers and clinicians who are not familiar with biomaterial collection for cell source derivation. Note that cell lines will be identified by NINDS for inclusion after the award is made. Present plans include: 1) the de novo generation of 15-25 iPSC lines per year; 2) the generation of 20-30 fibroblast lines per year, either through de novo establishment from skin biopsies or through limited expansion of NINDS approved lines; and 3) the banking of 40-50 peripheral blood mononuclear cell (PBMC) samples per year. All iPSC, fibroblast and PBMC sources developed through this resource will be approved by the NINDS Scientific Program Director prior to commencement of work.
• It is anticipated that PBMC samples will be received within 24 hours of each subject visit. 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.
• Characterization, quality control and assurance measures. Describe methods for the development, expansion and characterization of a master bank and distribution lot for iPSC and fibroblast cell resources. Describe any sample-specific characterization and sample-type specific quality assurance procedures planned. Describe genotyping services available for both routine screening of known variants for certain sample types, as well as whole genome sequencing, ancestral informative characterization, or other approaches for genotyping sample collections. For cell lines where genomic modification will be performed, both the parent and modified lines will undergo whole genome sequence characterization. Describe planned sample tracking methods (such as bar-coding or SNP genotyping).
• Control lines. Describe methods for providing appropriate and high-quality controls for disease iPSC lines. Planned strategies should go beyond developing controls by matching age and sex.
• De novo derivation of iPSC and fibroblast cell sources. Describe strategies to be used for the de novo derivation of iPSC and fibroblast cell resources including the handling and quality assessment of the starting sample types (e.g., skin biopsies, PBMCs, other cell sources). Propose detailed plans for characterization, quality assessment, preparation, storage and distribution of various cell sources. Plans should describe how the proposed methods and processes will ensure the distribution of high-quality, well-characterized samples to the biomedical research community for appropriate uses. Plans should also describe how innovation in derivation methods, sample handling or characterization will be incorporated over the time course of this award. Given the significant variation in expertise at sites that will contribute samples, describe any expectations and training plans for local processing and handling of various sample types at the collection sites.
• Genome Editing. Describe strategies for genome editing that will enable the development of isogenic lines carrying novel mutations or corrections of known mutations. Strategies should include the quality assessment of these lines, including whole genome sequencing of the parent line and corresponding lines that have been genetically modified.
• Maintenance and Storage. Describe plans for maintenance of the existing collection and for re-expansion of samples when needed. Describe safeguards against accidental loss of the collection, including storage of duplicates at a remote site, freezer failure back-up plan, and other contingencies. Describe safeguards to prevent temperature changes when freezers are accessed, alarm systems and procedures, and other safeguards against sample loss. If samples are to be stored under a subcontract, they shall not be distributed or used by the subcontractor without prior NINDS written authorization. Lost samples may be re-collected at the expense of the awardee, at the request of NINDS.
• Additional existing archival sample collections from academics or industry may be submitted to the repository if specific conditions for NINDS approval are met and upon NINDS request.
• Distribution of human iPSC and fibroblast lines. Describe the approach for receiving requests for samples from various requestors, how requests 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, and strategies to prevent samples not being collected by the recipient upon arrival (to the extent possible). Note: these plans should include both US and international recipients. It is anticipated that world-wide distribution will include 200-300 cell lines per year.
• Describe innovation in cell banking that may accelerate research and standardization of resources through the development and distribution of cell source derivatives such as, but not limited to iPSC-derived neural precursor cell sources. In the description include standardization and quality assessments that will be applied to cell source derivatives to ensure the distribution of a standardized product.

Additionally, applicants should:

• Describe how the details of laboratory standard operating procedures will be shared and publicized.
• Describe plans for the Institutional Review Board (IRB) that will review the use of materials that are considered Human Subjects.
• Describe timelines for: processing from sample receipt to storage, sample request to shipping, protocol deviation to reporting to NINDS, and other activities. Where possible, integrate timelines for these activities into project milestones.

Data Repository:

The applicant must describe plans for maintaining a computerized data management system that facilitates retrieval of sample information about NINDS Repository iPSCs, PBMCs and fibroblast cell lines. The plan must present a system that is effective for quality control, tracking of samples, fulfilling orders, billing for cost reimbursement, shipping, and maintaining inventories. Data management plans should also include a back-up system to protect against accidental loss of valuable data. The design and development of the database should be such that it provides a user-friendly accounting of the repository's inventory, and ensures data integrity, accuracy, and security. Such information should include but is not limited to: a global unique identifier (GUID), sample type, links to associated cell resources, de-identified clinical information, a certificate of analysis, including QC data for the lines, cell retrieval and maintenance information, and inventory availability. Design of the data repository must allow for easy sharing of the data with other repositories as a means to increase visibility and availability of the cell lines and should include the use of NINDS Common Data Elements (CDEs; https://www.commondataelements.ninds.nih.gov/#page=Default).

Applicants must address their strategy to provide the following:

• A data management plan that includes inventory, catalog, and other necessary information for researchers to access fibroblast, PBMCs and iPSC lines and related de-identified clinical information
• A public web-based interface with the research community to promote the goals of the NINDS Human Cell Resource and Data Repository and to provide tools and information for the collection and use of these cell lines, including ordering samples
• Data management strategies to facilitate easy searching, identification, and requesting of cell lines and their associated data
• Manage data associated with the human cell lines including integration of de-identified clinical data from other databases or resources, including NINDS CDEs.

Data Management. Data management activities must dovetail with a variety of other data management resources in academic and industry settings. Data management capabilities must be: 1) nimble in sharing inventory and cataloging data on a regular basis; 2) able to receive de-identified clinical and other sample associated data (ensuring data follows the FAIR data principles (findable, accessible, interoperable, and reusable); 3) able to track and notify submitters and requestors; 4) able to incorporate current common and disease-specific NINDS CDEs; 5) able to fully share data with the NINDS Program staff and their designees as appropriate. Dedicated staff with IT and data management experience must be available for trouble-shooting any data management aspects of the project.

Web-based Catalog. Describe plans for a Web-based electronic catalog that lists the available cell lines with associated information about them, including a NINDS GUID, detailed phenotype and molecular genotype data, cell culture history, cell lines and DNA available from family members, pedigree diagrams, and chromosome ideograms, and links to related genetic databases. This catalog will be hosted by the awardee, as well as other databases that increase the visibility of the cell lines available. Catalog information must include a list and explanation of the policies governing the submission and requesting of samples. Provide a strategy of tracking performance of the resource including metrics such as distribution, website traffic, publications citing the source, and other utilization of the resource.

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 IT and data management related concerns, but the entire collection project. For example, this help-desk function would provide support to biomedical researchers who submit samples, submit data, search for samples, have technical questions regarding the submission, or who need assistance with decisions on ordering. The customer service plan must include timelines regarding turn-around time on any query.

Publicizing Repository Collections. Describe plans to publicize repository collections. Efforts may include publishing notices and 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 repository, 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. These activities must be directed towards scientists and towards the public being served, i.e., those with neurological disorders and their friends and families.

Additional Application Elements:

Applicants must also address each of the following key elements:

Milestones. Specific milestones must be presented that will need to be met in order to accomplish the aims. 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. Achievement of milestones will be evaluated by NINDS, and funding of non-competing award years will depend on milestone accomplishment.

• Describe the research communities served in terms of providing access to iPSC, fibroblast or PBMC lines, and any unique skills, tools, or experience relevant to the proposed work that are not already detailed in the Biosketch. Describe particular abilities in technology advancements and standardization in iPSC resource development, development and characterization of genetically modified iPSC lines, and iPSC derivatives.
• 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 neither be onerous nor provide a disincentive for use of the collection.
• Intellectual Property Rights. Provide a strategy for resource management that addresses the need/requirement for licensing agreements that enable the broad distribution of NINDS repository cell resources to both academic and industry investigators. These licensing agreements should address and provide reasonable solutions for any intellectual property rights that limit the use of the NINDS cell repository cell resources and create egregious demands on the intended cell source recipient or their institution.

Letters of Support: Statements of Institutional Commitment, if appropriate, should be included in this section. In addition, a letter from the applicant must 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 biospecimens from any human subject unless that subject or subject's representative has given signed, explicit consent and the consent follows the language required for broad distribution, banking and utilization as established by NINDS.

The following modifications also apply:

• Consistent with achieving the goals of this repository, applications are required to describe a Data Sharing Plan. The data sharing plan should minimally include the following elements:

  • comprehensive and verified databases that contain all clinical, diagnostic, and genotypic information;
  • high-quality cell lines, from which DNA will be extracted and stored;
  • mechanisms by which all data and any biomaterials are widely distributed to qualified investigators in the scientific community;
  • a protocol for wide dissemination of these data and applicable biomaterials;
  • a timetable for distribution
• Applicants are expected to address how cell characterization data and biomaterials will be made publicly available. Consistent with NIH Genomic Data Sharing (GDS) policy, applicants must also provide a GDS plan for sequencing data generated.

• Resource development 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.

• Applications which do not describe plans and resource capability to provide all the required functions and services will be considered incomplete to this FOA.

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 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.

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).All instructions in the SF424 (R&R) Application Guide must be followed.

3. Unique Entity Identifier and System for Award Management (SAM)

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

4. Submission Dates and Times

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

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

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

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

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

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.

7. Other Submission Requirements and Information

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 How to Apply Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

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

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

See more tips for avoiding common errors.

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

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process. Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

For this particular announcement, note the following:

Applications responsive to this FOA support the development, maintenance and distribution of human cell resources including iPSCs and fibroblasts that will play a significant role in advancing basic science and drug discovery efforts for neurological disorders supported by NINDS. Accordingly, since the c ell lines developed will be broadly distributed to the research community, reviewers will emphasize the technology capabilities, quality assurance standards and the level of innovation that will be applied to ensure the research value of this cell resource.

Significance

Does the proposed repository address the needs of the research resource that it will serve? Is the scope of activities proposed for the repository appropriate to meet those needs? Will successful completion of the aims bring unique advantages or capabilities to the research resource? What will be the effect of these research resources on other scientific activities that drive this field?

Investigator(s)

Are the PD(s)/PI(s) and other personnel well suited to their roles in the repository? Do they have appropriate experience and training, and have they demonstrated experience and an ongoing record of accomplishments in managing critical repository functions? Do the investigators demonstrate significant experience with coordinating collaborative basic or clinical research? If the repository is multi-PD/PI, do the investigators have complementary and integrated expertise and skills; are their leadership approach, governance, plans for conflict resolution, and organizational structure appropriate for the repository?

Specific to this FOA:

Does the applicant/organization have a demonstrated track record in stem cell biology, including in cell source quality control, characterization and distribution?

To what extent have the PD(s)/PI(s) demonstrated experience in providing high-quality research resources and services for neurological disorders to the scientific community?

To what extent are the PD(s)/PI(s) committed to the principles of free and open sharing of research resources for neurological disorders?

Does the applicant have experience in data management and web-based IT design and support, including a customer service component?

Does the applicant have a track record which would facilitate understanding and serving the needs of academic communities?

Is there evidence that the investigative team will provide leadership in the field of iPSC resources scientifically?

Does the investigator have experience in genome editing, whole genome sequencing, and generation of stem cell derivatives such as neural precursor cells and differentiated CNS cell populations and characterization?

Innovation

Does the application propose novel organizational concepts or management strategies in coordinating the research resource the repository will serve? Are the concepts, strategies, or instrumentation novel to one type of research program or applicable in a broad sense? Is a refinement, improvement, or new application of organizational concepts, management strategies or instrumentation proposed? To what extent does the proposed repository employ novel concepts, approaches, or methods for the production and sharing of research resources, the integration of biorepository data into a central warehouse, the integration of that data with other public resources, and the implementation of a single user-friendly, web-based access portal?

Specific to this FOA:

Is there evidence that new technologies and innovative approaches will be adopted as appropriate to assure high-quality characterization and preparation of cell resources, and to assure that relevant de-identified clinical data and related cell source characterization will be easily accessible by biomedical researchers?

Is there a high likelihood that the activities proposed will be nimble enough to stay current to the greatest extent possible, given rapid advances in iPSC technology, genome editing, and information technologies?

Is there evidence that innovative approaches will be utilized to support the characterization of the sample collection?

Is there evidence of innovative approaches to outreach to the scientific community?

Approach

Are the overall strategy, operational plan, and organizational structure well-reasoned and appropriate to accomplish the goals of the research resource the repository will serve? Will the investigators promote strategies to ensure a robust and unbiased scientific approach across the resource, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the resource is in the early stages of operation, does the proposed strategy adequately establish feasibility and manage the risks associated with the activities of the resource? Are an appropriate plan for work-flow and a well-established timeline proposed? Have the investigators presented adequate plans to ensure consideration of relevant biological variables, such as sex, for studies of vertebrate animals or human subjects? Are plans for publicizing repository collections appropriate and likely to promote awareness of repository collections to the scientific community and/or aid in recruitment of additional cell lines to the repository in a cost-effective manner? Is the cost recovery plan appropriate for the cell sources provided and in line with other cell source resources?

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?

Specific to this FOA:

Are repository collection acquisition plans appropriate well-reasoned, timely, and appropriate?

Are confidentiality and informed consent adequately addressed?

Are the design of quality control, data collection, and analysis appropriate? Does the applicant describe a strategy for incorporating high-quality controls for disease iPSC lines?

Does the proposed database provide a user-friendly accounting of the resource's holdings and ensure data integrity, accuracy, and secure cyberinfrastructure? Is the plan for a back-up facility appropriate? Are plans for customer service likely to facilitate acquisition of cell resources by academic and industry researchers?

Does the application appropriately address evaluation of processes and implementation of improvement plans of the resource's procedures and programs when feedback is given via users or the NIH staff, and is this plan nimble and flexible?

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

Does the application give evidence of how protocols will be shared, including via web-based and other methods?

Are reasonable, appropriate, and timely methods described to track and monitor repository use, both submitting and accessing, and the outcomes of such use, including data and publications?

Does the application give examples of how scientific advances will be incorporated into the project?

Does the application provide an adequate strategy to address any intellectual property issues around current technologies used for iPSC derivation and genomic editing and does this strategy minimize the burden to the user of the cell resource?

Does the application provide appropriate milestones that will need to be met to accomplish the work set out above in a five-year time frame?

Environment

Will the institutional environment in which the repository will operate contribute to the probability of success in facilitating the research resource it serves? Are the institutional support, equipment and other physical resources available to the investigators adequate for the repository proposed? Will the repository benefit from unique features of the institutional environment, infrastructure, or personnel? Are resources available within the scientific environment to support electronic information handling?

Specific to this FOA:

Has an alternative location been identified for storing duplicate samples in case of natural or man-made disaster?

Has a plan been delineated in case of equipment or other failure which might jeopardize samples?

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

Does the proposed center have a dedicated stem cell facility for high-throughput production, handling and quality control of iPSCs?

To what extent does the proposed facility have capabilities for in-house high-throughput nucleic acid extraction and cell line generation from primary source cells (i.e. FCL, CPL, ERYB, LCL) with quality control?

Protections for Human Subjects

For research that involves human subjects but does not involve one of the 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 categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

Inclusion of Women, Minorities, and Individuals Across the Lifespan

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 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.

Vertebrate Animals

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.

Biohazards

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

Resubmissions

Not Applicable

Renewals

For Renewals, the committee will consider the progress made in the last funding period.

Revisions

Not Applicable

Applications from Foreign Organizations

Not Applicable

Select Agent Research

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

Resource Sharing Plans

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

Authentication of Key Biological and/or Chemical Resources:

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.

Budget and Period of Support

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

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by the National Institute of Neurological Disorders and Stroke (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.

• May undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.
• Will receive a written critique.

Applications will be assigned to the National Institute of Neurological Disorders and Stroke (NINDS)

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.
• Commitment of the PD(s)/PI(s) to broad data and sample sharing and the long-term scientific mission, goals, and objectives of the NINDS.
• Consideration of the plans to make biomaterials and data broadly available in a rapid manner to the scientific research community.

3. Anticipated Announcement and Award Dates

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

Section VI. Award Administration Information

1. Award Notices

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.

2. Administrative and National Policy Requirements

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.

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.

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 https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/index.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-individuals/section-1557/index.htmlhttps://www.hhs.gov/civil-rights/for-providers/laws-regulations-guidance/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see https://www.hhs.gov/civil-rights/for-individuals/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.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.

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:

• Planning, organizing, coordinating and administering the described project activities
• Performing all activities within the scope of the research strategy specified in the application including setting project milestones. The awardee agrees to accept close coordination, cooperation, and participation of NIH staff in those aspects of scientific and technical management of the study as stated in these terms and conditions.
• Organizing Scientific Advisory Committee meetings for the NINDS Human Cell and Data Repository
• Providing written reports as requested to NINDS Program staff as well as biweekly supplementary status reports
• Participating in group activities including resource supported Scientific Advisory Committee calls and subcommittees as needed.
• Preparing abstracts, presentations, and publications and collaborating in making the public and scientific community aware of this resource
• Awardees will retain custody of and have primary rights to the software that is developed under this award, subject to Government rights of access consistent with HHS, PHS, and NIH policies.

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

• Serving as a liaison to help coordinate activities of the awardee, including acting as a liaison to other NIH Institutes/Centers sponsored biobanks and databases as needed and as an information resource for the awardees.
• Substantial involvement in coordinating the activities of the awardee with other NIH-sponsored biobanks and databases as necessary
• Participation in NINDS Human Cell and Data Repository Scientific Advisory Committee meetings
• Assisting awardees in the development, if needed of policies for dealing with situations that require coordinated action
• Providing advice in the management and technical performance of the award
• Assisting in promoting the availability of data and resources developed in the course of this project to the scientific community at large

Additionally, an NINDS Program Official will be responsible for:

• Normal scientific and programmatic stewardship of the award and will be named in the award notice.
• Monitoring the project on a regular basis. Monitoring may include regular communication with the PI and awardee staff, periodic site visits or meetings for discussion with the awardee research team, fiscal reviews, and other relevant stewardship matters.
• Formally evaluating the project on a yearly basis. The yearly evaluation will be based on the non-competing application and recommendations of the NINDS Project Scientist.

NINDS reserves the right to terminate or curtail the resource (or an individual component of the resource) in the event of inadequate progress, data reporting, or insufficient use of this resource.

Areas of Joint Responsibility include:

• Clarifying, negotiating, and finalizing the milestones and timelines
• During the course of the award period, the awardee(s) may be invited to meet with NINDS Project Scientist, and other uninvolved experts in Bethesda, MD, to review scientific progress, the use of the resource, and/or relevant NIH or HHS policies relevant to the resource.
• Existing policies on distribution and appropriate use of repository samples, as outlined in the NINDS Cell and Data Repository Material Transfer Agreement and other established NIH/NINDS policies, will be maintained in the new project period. Changes to existing policies may be developed jointly by the awardee and NINDS staff and must be in compliance with relevant HHS, PHS, and NIH policies.
• The government retains ownership of all cell lines and data associated with the samples in the current repository collection and those developed under this project. NINDS and the awardee will jointly develop a plan to transfer repository cell lines and data to a new repository operator in the event that the awardee does not successfully compete for a subsequent project period.

NINDS Human Cell and Data Repository (NHCDR) Scientific Advisory Committee

The NINDS Human Cell and Data Repository Scientific Advisory Committee will meet annually, along with teleconferences as needed, to review progress, advancements, innovations and external demand for the NINDS Human Cell and Data Repository and identify areas within the Cell and Data Repository Program that could benefit from additional reporting, technology development, resources provided or infrastructure. Members of the Scientific Advisory Committee will be selected by the NHCDR PI after consultation with NINDS.

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. The three members will be: a designee of the awardee, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two. 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.

3. Reporting

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.

Section VII. Agency Contacts

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 instructions, 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]

Daniel Miller, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-5680
Email:[email protected]

Christine Swanson-Fischer, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-5680
Email: [email protected]?

Chief, Scientific Review Branch
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9223
Email: [email protected]

Tijuanna DeCoster, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9231
Email: [email protected]

Section VIII. Other Information