It is critical that applicants follow the Research (R) 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

Purpose

The National Institutes of Health (NIH) participating Institutes and Centers (ICs), in coordination with the U.S. Food and Drug Administration (FDA), invite cooperative agreement (U01) applications that will support investigator-initiated clinical research studies aimed at furthering the field of regenerative medicine (RM) using adult stem cells. These applications are expected to focus on innovative projects that propose solutions to widely recognized issues in the development of safe and effective RM therapies, contribute an enhanced understanding of stem cell product attributes, and promote data sharing. Emphasis will be given to projects that address critical issues in product development relevant for regulatory submissions. Areas of focus may include improved tools, methods, standards, or applied science that support a better understanding and improved evaluation of in-depth product characterization, manufacturing, potency, identity, quality, safety, in vivo function and integration, or effectiveness.

Toward these ends, the NIH will consider applications for late-stage preclinical research studies involving adult stem cells in the context of generating or supplementing the necessary evidence for clinical development, including, but not limited to, the submission of an Investigational New Drug (IND) or Investigational New Device Exemption (IDE) package; or to support such research conducted under an authorized IND or IDE. Successful applicants proposing the use of adult stem cells as a clinical intervention will be asked to make available representative samples of the source stem cell line and clinical-grade stem cell product for in-depth and independent characterization through the RM Innovation Catalyst.

Background

This FOA, issued as part of the Regenerative Medicine Innovation Project (RMIP), represents one step in fulfilling a new statutory provision set forth in the 21st Century Cures Act. Given the potential of RM to enhance human health and treat disease, in the 21st Century Cures Act Congress authorized a total of $30 million in fiscal years 2017 through 2020 for the funding of clinical research to further the field of RM using adult stem cells, including autologous cells. The 21st Century Cures Act stipulates that awards must be contingent upon the recipient procuring non-Federal contributions in an amount not less than $1 for each $1 of Federal funds (total Direct and Indirect/Facilities and Administrative (F&A)) costs provided in the award (i.e., a matching funds requirement). Additional information is provided in the FAQs and Matching Requirement section below.

Research projects responsive to this FOA are expected to involve both of the following: (1) human subjects or material of human origin, such as cells, tissues, and specimens; and (2) human stem cells that are not of embryonic or fetal origin. Research projects involving induced pluripotent stem (iPS) cells may be supported if the cells used to generate the iPS cells were not of fetal or embryonic origin. Applicable research on adult human stem cells may encompass, for example, research on biologics (e.g., growth factors, cytokines) and biomaterials (e.g., extracellular matrix, scaffolds) that stimulate host adult stem cell self-renewal, proliferation, differentiation, and/or function or otherwise directly act upon adult stems cells to support innate host healing mechanisms, treat disease, and/or restore function. Funding could be used, for example, for the appropriate chemistry, manufacturing, and controls development to support the production of such products for clinical trials using phase-appropriate current good manufacturing practices (cGMP). Funds may not be used for research involving human cells of embryonic or fetal origin.

This FOA seeks highly meritorious research projects proposing to explore and enable the development of safe and effective RM interventions. NIH expects that proposed projects will:

• Address critical issues relevant to clinical research and regulatory submissions including those related to product development. Areas of focus may include improved tools, methods, standards, or applied science that support a better understanding and in-depth characterization of product manufacturing, quality, safety, or effectiveness;
• Help to significantly advance the field of RM by addressing a well-recognized challenge in clinical development, including the development and evaluation of safe and effective RM products; and
• Contribute to breadth/diversity of RM science.

Regenerative Medicine Innovation Catalyst

To catalyze the efficient development of safe and effective adult stem cell-based therapies and further the field of RM, NIH intends to establish an RM Innovation Catalyst to provide critical services to RMIP awardees (for both non-clinical trial research and clinical trials). Toward these ends, the RM Innovation Catalyst will offer, at no additional cost, regulatory support services and may also provide assistance for the development of phase-appropriate clinical-grade product. Applicants interested in the services offered by the RM Innovation Catalyst are requested to contact their NIH Scientific/Research Contact as early as possible in the application process for further details regarding these services.

In addition, to inform future studies and ultimately advance the field, applicants will be expected to provide representative samples of the source stem cell line and clinical-grade stem cell product for in-depth characterization by the RM Innovation Catalyst. The RM Innovation Catalyst will:

• Conduct in-depth and independent characterization of the source stem cell line and stem cell products being developed.
• Provide a platform for sharing and analysis of clinical trial (if applicable) and cell product characterization data, thereby potentially enabling correlation of stem cell attributes with clinical outcomes. (See Resource Sharing Plan)
• Ultimately create a foundation for enhancing our understanding of clinical outcomes and refining production methods.

The in-depth characterization assays conducted by the Catalyst will be performed in parallel with the study or post-hoc. Because in-depth characterization assays may identify cell attributes for which the clinical significance is not currently known, these results are not intended to inform decisions during the conduct of the study, nor are they intended to factor into the normative oversight requirements and processes for the source study. Assay results will be returned to the study investigators as they become available. In order to accelerate the field and inform oversight of future studies, assay results will be made available to the broader research community via the Catalyst one year following the end of award (or as appropriate).

See relevant FAQs for additional details.

Collection and Sharing of Resources

Materials

Awardees will be required to make available representative samples of the source stem cell line and clinical-grade stem cell product for in-depth and independent characterization. Details regarding the provision of stem cell samples will be communicated to awardees by NIH staff. Results of cell characterization will be provided to the study investigator when available and are anticipated to be made available to the research community one year following the end of award.

Research Examples

Applicants are strongly encouraged to submit research applications that demonstrate potential to catalyze sustained and accelerated development of the RM field through contributing to the knowledge critical for clinical testing, stem cell characterization and authentication, cGMP compliant stem cell production, in vivo stem cell tracking and monitoring, data standards development, and data sharing. It is expected that submitted applications will address the following:

• Preclinical studies that contribute to conducting clinical trials that address specific clinical indications;
• Testing human adult stem cells in well-developed animal models;
• Monitoring stem cell function and integration in vivo;
• Methods for in-depth stem cell characterization and deep fingerprinting, and utilization of standards;
• Interactions with FDA regarding a future IND or IDE application (such as having had a pre-IND meeting and other communications);
• Further development of standards and cGMP for adult stem cell-based RM products;
• Leveraging extant cell production facilities for product preparation and qualification; and
• Contributing to a better and shared understanding of current technical and operational barriers as well as regulatory science issues and how to overcome them.

Matching Requirement

An application funded under this announcement is required to match all federally awarded dollars (total costs: direct costs and indirect costs including facilities and administrative costs) with at least an equal amount (1:1) of non-Federal contributions, as mandated by the 21st Century Cures Act. Qualifying non-Federal contributions may include state and local funding not originating from Federal funds, private-sector investments, in-kind contributions, and donations from foundations. See 45 CFR 75.306, as well as relevant FAQs, for additional details. The applicant will be required to demonstrate that funds and in-kind contributions are committed or available at the time of, and for the duration of, the award. Applications must identify the source, type, and amount of funds proposed to meet the matching requirement and explain how the value of in-kind contributions was determined. Applications must also include letter(s) of support confirming that the required matching contributions (cash or in-kind contributions such as salary, consultant costs, equipment) are available. See additional details and instructions in in Section IV.2 and Section VI.3.

Definitions

Adult stem cells are defined, for the purpose of this FOA, as stem cells (including iPS cells) that are not of fetal or embryonic origin or derived from embryonic or fetal stem cells.

Total project budget is the total amount of financial resources allocated for the project. This includes Federal funds, as well as cash and in-kind contributions from non-Federal sources for direct and indirect expenses.

Total Federal budget is the Federal share of the total project budget.

Applications Not Responsive to this FOA

The following types of applications will be considered non-responsive to this FOA:

• Any research using human embryonic or fetal stem cells. Such projects are non-responsive.
• Applications that do not include a plan to make available representative samples of the source stem cell line and clinical-grade stem cell product for in-depth characterization by an NIH-designated core facility (RM Innovation Catalyst). Such applications are incomplete. See additional details and instructions in Section IV.2.
• Applications that do not include a letter(s) of support confirming that the required matching contributions (cash; in-kind contributions such as salary, consultant costs, equipment) are available. Such applications are incomplete; see additional details and instructions in Section IV.2.

Consultation

Potential applicants to this FOA are strongly encouraged to consult with the Scientific/Research Contact(s) for the area of science for which they are planning to develop an application. Early contact is encouraged as it provides an opportunity for NIH staff to discuss the scope and goals of the project and to provide guidance to applicants.

For more information please refer to specific FAQs for the FOAs.

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

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

Higher Education Institutions

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

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

• 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)
• 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 requires cost matching as defined in the NIH Grants Policy Statement. More information on the cost matching requirements is in Section IV.2 R&R or Modular Budget.

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).

Buttons to access the online ASSIST system or to download application forms 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.

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

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

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

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

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

The letter of intent should be sent to:

Director, Office of Scientific Review
Division of Extramural Research Activities
National Heart, Lung, and Blood Institute (NHLBI)
6701 Rockledge Drive, Room 7214
Bethesda, MD 20892-7924 (Express Mail Zip: 20817)
Telephone: 301-435-0270
Email: [email protected]

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

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing 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. Additional instructions include:

Applicants must submit budgets that clearly document the total costs, the source and amount of matching funds, and how valuation was determined in the case of in-kind contributions, as well as the Federal and Institutional (non-Federal) components of the budget.

Include budget support for the PD/PI to participate in an NIH-held RM innovation meeting or workshop once each budget year in the Washington, DC/Metropolitan area.

Cost Matching Requirement

Cost matching is required for applicants responding to this FOA. The awardee is required to match (at least 1:1) the total Federally-awarded amount (total Direct and Indirect/F&A costs). Institutions must be able to document their actual contributions, which may include in-kind contributions, to the project and provide assurances that the organization(s) are committed to providing the funds and resources for their share of the project.

Federal funds may not be used as a source of matching funds. Generally, cost matching requirements may not be met from the following sources:

• Costs borne by another Federal grant or sub award
• Costs or contributions toward cost sharing on another Federal grant, a Federal procurement contract, or any other award of Federal funds
• Cost of services or property financed by income earned by contractors under a contract from the recipient (or sub recipient)
• Program income
• Patient incentives

Applicants must submit budgets that clearly document the total costs, the source and amount of matching funds, and how valuation was determined in the case of in-kind contributions, as well as the Federal and Institutional (non-Federal) components of the budget.

Budget Justification: A total project budget (i.e., the requested budget plus the cost-matching budget) must be provided and must document the cost-matching (non-Federal) component and the Federal (non-cost matching) component. The amount of matching is subject to adjustment based on total allowable costs incurred. All costs and contributions used to satisfy the matching requirement must be documented by the recipient, including how the value for in-kind contributions was determined, and are subject to audit. The cost matching requirement is not negotiable.

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:

Research Strategy

Describe how the proposed project will:

• Advance the field of RM and contribute to foundational knowledge
• Address well-recognized challenges in clinical development
• Evaluate safety and effectiveness RM products

Describe how the proposed project will address critical issues relevant to clinical research and regulatory submissions, including those related to RM product development (e.g., improved tools, methods, standards, or applied science that support a better understanding and improved evaluation of in-depth product characterization, manufacturing, potency, identity, quality, safety, in vivo function and integration, or effectiveness).

Letters of Support: Non-Federal sources of matching or partial funding must provide Letter(s) of Support signed by an authorized organization representative (AOR).

A non-Federal funding entity with a peer review process that cannot be concluded by the application deadline but that will be concluded in time to meet the Post Submission Materials, may provide a letter of support indicating it is considering a funding request from the applicant for the project. The letter must be signed by an AOR and must state the name of the applicant, project title, dollar amount or value of the in-kind contribution under consideration, and the date a decision will be made. A letter indicating the funding decision must be provided to NIH no later than December 10, 2018.

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 modifications:

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.
• To be considered complete, applications are expected to include a plan to make available representative samples of the source stem cell line and clinical-grade stem cell product for in-depth and independent characterization, as appropriate and consistent with achieving the goals of the program.

Appendix:

Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

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

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

Study Record: PHS Human Subjects and Clinical Trials Information

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

Delayed Onset Study

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

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

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

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

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

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

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

This initiative is not subject to intergovernmental review.

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

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

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

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

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

Important reminders:

All PD(s)/PI(s) 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 the policy. Amended letter(s) of support indicating whether an applicant successfully competed for non-Federal funds will be accepted as post-submission materials if received by December 10, 2018. Any instructions provided here are in addition to the instructions in the policy.

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

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? Is there a strong scientific premise for the project? 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?

Specific to this FOA:

How likely is it that the proposed project will significantly advance the field of RM by contributing to foundational knowledge while addressing a well-recognized challenge in clinical development, and evaluation of safe and effective RM products? To what extent does the application address critical issues relevant to the fundamental scientific understanding of the safety, quality, and effectiveness of adult stem cell-derived products used in clinical research and regulatory submissions, including those related to RM product development (e.g., improved tools, methods, standards, or applied science that support a better understanding and improved evaluation of in-depth product characterization, manufacturing, potency, identity, quality, safety, in vivo function and integration, or effectiveness)?

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

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?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

If the 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?

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

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

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

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

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 Data Sharing Plan (GDS). In particular, reviewers will comment on the following: Plan to make available representative samples of the source stem cell line and clinical-grade stem cell product to an NIH-designated entity (RM Innovation Catalyst) for in-depth and independent characterization.

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

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

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by the National Heart, Lung, and Blood Institute, 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 on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Board. The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.
• All regulatory requirements have been met.

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

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

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

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

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

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

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

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

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

For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see 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 http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and https://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 http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at 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.

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

Cooperative Agreement Terms and Conditions of Award

NIH Cooperative Agreements are subject to terms and conditions in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budgets (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 grants 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 primary responsibility for:

The PD(s)/PI(s) will have the primary responsibility to define objectives and approaches, and to plan, conduct, analyze, and publish results, interpretations, and conclusions of their studies.

Awardees agree to participate in the overall coordination of research efforts. This participation includes collaboration and consultation with NIH staff, and the sharing of information, data, and research materials, as appropriate and consistent with achieving the goals of the research program.

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

The NIH Program Official will be responsible for the normal program stewardship of the cooperative agreement and will be in the Notice of Award. However, NIH may elect to have a dual-role approach where a single individual may act as both the NIH Project Scientist and Program Official. Final decision-making authority on matters of budgetary and funding actions, grants management actions, and management of intellectual property issues is assigned to NIH staff other than the Project Scientist. The responsibility for final decision making will be determined by Institute/Center leadership and may reside with senior management, separate organizational components, and/or oversight committees. Because it is anticipated that the Program Official will participate in activities that rise to a level of involvement (i.e., additional role as Project Scientist) that results in conflicts of interest, for example, co-publication, other staff members such as direct line supervisors and/or other Senior NIH Program management staff will serve as agency Program Officials and will be responsible for the normal scientific and programmatic stewardship of the award.

The NIH reserves the right to phase out or curtail the study (or an individual award) in the event of (a) substantive changes in the agreed-upon methodologies and tools with which NIH cannot concur, (b) human subject ethical issues that may dictate a premature termination, or (c) results that substantially diminish the scientific value of study continuation.

Areas of Joint Responsibility include:

Responsibilities that are shared between awardees and NIH staff will require close coordination. Responsibilities will be divided between awardees and NIH staff, as described above. Individual awardees will be required, in coordination with NIH staff, to develop and finalize plans for submission of their representative samples of the source stem cell line and clinical-grade stem cell product for in-depth and independent characterization as described in this FOA.

Awardees will retain custody of and have primary rights to their data developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies. NIH will partner with the PD/PI to ensure that the dataset preparation is congruent with requirements for NIH data repository datasets and associated documentation for submission to an NIH-designated data repository. Awardees should work closely with NIH staff to establish common data elements, data standards, metadata requirements, controlled vocabularies, and quality control metrics for all data to ensure that the data are Findable, Accessible, Interoperable, and Reusable (FAIR) to ensure the data and results are maximally useful to the public.

Study investigators are strongly encouraged to publish and to publicly release and disseminate results, tools, resources and other products of the study, in accordance with the study protocols and governance. It is expected that all methods, analyses, software, and algorithms will be made available in a timely matter to the scientific community. Within 3 years of the end of the period of NIH support for the project, data not previously released and other study materials or products not previously distributed are expected to be made available to individuals who are not study investigators in accordance with the NIH IC Data Sharing Policy.

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 awardee, an 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.

Matching

Matching funds (1 to 1 match) will be required (as per the 21st Century Cures Act) for the specific project awarded in each budget period (i.e., at least 100% match). Matching funds must be non-Federal funds set aside for this project and are available from the source(s) identified in the application, as committed to by the recipient. Cost matching will be evaluated on an annual basis by the awarding office to ensure that this requirement is being met. Compliance with the matching requirement must be verified in each budget period by showing the amount of Federal and non-Federal contributions, and must be documented in the annual FFR.

The Recipient agrees that if matching funds become unavailable and replacement matching is not secured within 90 days of them becoming unavailable, the award is subject to being phased out at the end of those 90 days. During that period no Federal funds may be drawn down, pending receipt a new matching agreement. Failure to notify the NIH may result in disallowed costs during any period in which matching funds are not available, and other enforcement actions as described in the NIH GPS.

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

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

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

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

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

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

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

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

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

Martha Lundberg, Ph.D.
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0513
Email: [email protected]

Steven Becker, Ph.D.
National Eye Institute (NEI)
Telephone: 301-496-2234
Email: [email protected]

Candace Kerr
National Institute on Aging (NIA)
Telephone: 301-827-4474
Email: [email protected]

Nancy Bridges, M.D.
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-627-3535
Email: [email protected]

Fei Wang, Ph.D.
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Telephone: 301-594-5055
Email: [email protected]

Rosemarie Hunziker, PhD
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Telephone: 301-451-1609
Email: [email protected]

Nancy L. Freeman, Ph.D.
National Institute on Deafness and Other Communication Disorders (NIDCD)
Telephone: 301-402-3458
Email: [email protected]

Nadya Lumelsky, Ph.D.
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: 301-594-7703
Email: [email protected]

Deborah K. Hoshizaki, Ph.D.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-594-7712
Email: [email protected]

David Panchision, Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 301-443-5288
Email: [email protected]

Timothy LaVaute, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-3765
Email: [email protected]

Philip J. (P.J.) Brooks, Ph.D.
National Center for Advancing Translational Sciences (NCATS)
Telephone: 301-443-0513
Email: [email protected]

Director, Office of Scientific Review
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0270
Email: [email protected]

Anthony Agresti
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0166
Email: [email protected]

Karen Robinson Smith
National Eye Institute (NEI)
Telephone: 301-451-2020
Email: [email protected]

Mitchell Whitfield
National Institute on Aging (NIA)
Telephone: 301-496-1472
Email: [email protected]

Donna Sullivan
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-669-2979
Email: [email protected]

Andrew Jones
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Telephone: 301-435-0610
Email: [email protected]

Katie Ellis
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Telephone: 301-496-8521
Email: [email protected]

Christopher Myers
National Institute on Deafness and Other Communication Disorders (NIDCD)
Telephone: 301-435-0713
Email: [email protected]

Diana Rutberg
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: 301-594-4798
Email: [email protected]

Aretina Perry-Jones
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-594-8862
Email: [email protected]

Rebecca Claycamp
National Institute of Mental Health (NIMH)
Telephone: 301-443-2811
Email: [email protected]

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

Leslie Le
National Center for Advancing Translational Sciences (NCATS)
Telephone: 301-435-0856
Email: [email protected]

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

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75, and Section 1001 (b)(4)(D) of the 21st Century Cures Act (P.L. 114-255).