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

Purpose

The National Institutes of Health (NIH) participating Institutes and Centers, in coordination with the U.S. Food and Drug Administration (FDA), seek highly meritorious clinical trial applications proposing to explore and enable the development of safe and effective regenerative medicine (RM) interventions using adult stem cells. This Funding Opportunity Announcement (FOA), issued as part of the Regenerative Medicine Innovation Project, represents one step in fulfilling a statutory provision set forth in the 21st Century Cures Act. Applications submitted in response to this bi-phasic, milestone-driven cooperative agreement FOA are expected to propose highly innovative projects with a focus on solutions to widely recognized issues in the development of safe and effective RM therapies. Of particular interest are projects using RM products that have undergone appropriate product development and pre-clinical studies and have demonstrated readiness to advance into clinical trials.

This FOA seeks Phase I and beyond clinical trial applications that present a strong scientific rationale for the proposed clinical trial and a comprehensive scientific and operational plan. Trials must be relevant to the research mission of one or more participating NIH Institutes and Centers and meet the NIH definition of a clinical trial (see NOT-OD-15-015).

Before the time of award and if applicable, successful applicants must obtain an Investigational New Drug (IND) authorization or Investigational New Device Exemption (IDE) approval to administer the product to humans. 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 and clinical-grade stem cell-derived product for in-depth and independent characterization through the RM Innovation Catalyst.

Overview

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 & 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.

Objectives of this FOA

Applications submitted in response to this bi-phasic, milestone-driven cooperative agreement (UG3/UH3) FOA are expected to propose clinical trials (Phase I and beyond) that explore and enable the development of safe and effective RM interventions using adult stem cells that are not of embryonic or fetal origin with an emphasis on the following areas:

• 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 or phase-appropriate GMP and utilization of standards, in vivo stem cell tracking and monitoring, data standards development, and data sharing
• Readiness of the RM product for advancement into clinical trials under an IND/IDE application
• Contribution to the significant advancement of the field of RM by addressing well-recognized challenges in clinical development
• Critical issues relevant to clinical research and regulatory submissions, including those related to improved evaluation of product quality
• Provision of preliminary data, clinical and/or non-clinical study data, or information in the literature or citations regarding mechanism of action that support the scientific rationale and need for the clinical trial to test the proposed hypothesis or intervention
• Contribution to the breadth and diversity of RM science
• Use of existing research infrastructure such as clinical trial network(s) where possible
• Contribution to an improved and shared understanding of current technical and operational barriers as well as regulatory science issues in the field of RM and how to overcome them

Scope

Clinical trial applications must be relevant to the research mission of the participating NIH Institutes and Centers and are expected to involve both human subjects and human stem cells that are not of embryonic or fetal origin. Clinical trials involving induced pluripotent stem cells (iPSCs) may be supported if the cells used to generate the iPSCs 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 or support 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. Funds may not be used for research involving human cells of embryonic or fetal origin or those derived from embryonic or fetal stem cells.

Structure

Applications submitted in response to this FOA will utilize a bi-phasic, milestone-driven cooperative agreement (UG3/UH3) mechanism consisting of a start-up phase of up to one year (UG3) and a full enrollment and a clinical trial execution phase of up to four years (UH3). Applications are expected to address objectives for both phases (i.e., the UG3 and UH3 phase) and are strongly encouraged to use project management principles as appropriate.

Phases of Award

The UG3 phase will support the development of case report forms and other resources necessary for the performance of the trial; further development of study partnerships; and finalization and Institutional Review Board/Data and Safety Monitoring Board approval (as applicable) of the trial protocol, informed consent(s), manual of operations, and clinical trial project management plans. Applicants are strongly encouraged to address a comprehensive clinical trial project management plan that includes consideration of feasibility of trial launch, conduct, and completion, and on-time and on-budget performance milestones. The necessary products, devices, or other resources, should be obtained by the end of the UG3 award to allow for the successful launch and execution of the proposed clinical trial in the UH3 phase. In addition, it is expected that enrollment into the clinical trial will begin by the end of the UG3 phase or sooner. Subject to NIH funding availability and scientific priorities, UH3 awards will be made after administrative review with particular attention to the extent to which agreed-upon milestones have been met. If the UH3 is funded, an additional administrative review will be scheduled within the first two years of the UH3 to assess progress towards UH3 milestones, including enrollment milestones.

Milestones

Delineation of milestones is a key feature of this FOA. A milestone is defined as a scheduled event in the project timeline that signifies the completion of a major project stage or activity. All milestones must be reached by the end of each phase before transition occurs. Milestones are expected to be performance-based to enhance the likelihood that the trial will be completed on time and on budget. Satisfactory completion of UG3 milestones will be assessed administratively to determine eligibility to transition to the UH3 implementation phase. This FOA seeks applications that include a series of comprehensive milestones for completion of the clinical trial (UH3 phase) and provide contingency plans to proactively address potential delays in meeting the milestones. NIH staff, in collaboration with the awardee, will closely monitor progress at all stages, including milestones, accrual, and safety. If at any time the project fails to make satisfactory progress toward meeting milestones (e.g., recruitment falls significantly below the projected milestones for recruitment), NIH may consider ending support and negotiating a phase-out of the award. Continuation of the award is conditional upon satisfactory progress in meeting milestones and subject to the availability of funds.

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 has established an RM Innovation Catalyst to provide critical services to RMIP awardees. Toward these ends, the RM Innovation Catalyst will offer, at no 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, awardees will be expected to provide representative samples of the source stem cell and clinical-grade stem cell-derived 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 and stem cell-derived products being administered to research subjects
• Provide a platform for sharing and analysis of clinical trial 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 through the RM Innovation Catalyst will be performed in parallel with the clinical trial or post-hoc. This analysis is not intended to replace or supersede the investigator's characterization of the critical quality attributes of the cell product necessary to meet regulatory requirements. Rather, this analysis is intended to enhance the overall understanding of the biologic characteristics of these products. Moreover, in-depth characterization assays may identify cell attributes for which the clinical significance is not currently known and results may not be available during the conduct of the trial. For these reasons, in-depth characterization assay results are not intended to inform clinical decisions during the conduct of the clinical trial, nor are they intended to factor into the normative oversight requirements and processes (e.g., FDA, DSMB, IRB) 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 RM Innovation Catalyst one year following the primary completion date (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 and clinical-grade stem cell-derived 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 after the primary completion date (defined below) of the clinical trial (as appropriate).

Clinical Trial Data and Results

NIH will work with funded investigators to establish a schedule for submitting clinical trial data to the RM Innovation Catalyst and sharing those data with the research community.

• Deidentified individual participant-level data that have been cleaned and quality-controlled are expected to be provided to the RM Innovation Catalyst at least every six months and refreshed throughout the clinical trial; the final locked datasets are expected to be provided to the RM Innovation Catalyst no later than six months prior to the end of the award.
• Summary results are expected to be submitted to ClinicalTrials.gov within one year of the primary completion date (per regulation and NIH policy: https://clinicaltrials.gov/ct2/manage-recs/fdaaa, https://www.federalregister.gov/documents/2016/09/21/2016-22379/nih-policy-on-the-dissemination-of-nih-funded-clinical-trial-information).
• The deidentified individual participant-level locked dataset will be made available to the research community via the RM Innovation Catalyst through controlled access as appropriate in compliance with applicable Federal laws, regulations, and policies according to the following schedule:
  • Primary outcome data will be shared one year following the primary completion date.
  • The full dataset will be shared two years following the primary completion date.

Follow-up Data

Given the importance of understanding the clinical effects of the RM intervention, it is expected that awardees will conduct adequate post-treatment monitoring and evaluation of study participants during the trial to fully ascertain the effects of the treatment. Applicants are encouraged to consider what type of long-term follow-up data may be appropriate and address how they would plan to obtain such follow-up data.

Matching Requirement

An application funded under this announcement is required to match all federally awarded dollars (total costs: direct costs and indirect/F&A 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, cash or 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 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.

Primary completion date is the date on which the final subject was examined, interviewed, or received an intervention for the purposes of final collection data for the primary outcome, whether the clinical trial concluded according to the pre-specified protocol or was terminated early.

• 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/F&A expenses.

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

Applications that are incomplete or Not Responsive to this FOA

The following types of applications will be considered incomplete or non-responsive to this FOA and will not proceed to peer review:

• Studies that do not meet the NIH definition of a clinical trial
• Applications in which human subjects research is anticipated within the period of award but definite plans for the involvement cannot be described at the time of submission (i.e., Delayed Onset Human Subject Studies)
• Clinical trials using human embryonic or fetal stem cells or human embryonic or fetal stem cell-derived products
• Clinical trials that require but have not yet secured IND/IDE authorization/approval by the time of award
• Applications that do not include a plan to make available representative samples of the source stem cell and clinical-grade stem cell-derived product for in-depth characterization by an NIH-designated entity (RM Innovation Catalyst). Such applications are incomplete; see additional details and instructions in Section IV.2.
• Applications that do not identify the source and amount of funds proposed to meet the matching requirement and how the value for in-kind contributions was determined; 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 or 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 RMIP FOAs.

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)
• 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 Matching

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:

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

Facilities and Other Resources: Describe how the available infrastructure and performance site(s) will be leveraged to facilitate the efficient operation of the proposed clinical trial.

Describe the experience of key personnel in the conduct of clinical trial coordination and management, including success in meeting milestones and timelines, expertise in the content area of the proposed clinical trial, and expertise in biostatistics and clinical trial design. The experience of each PD/PI and all Key Personnel must be carefully documented, and roles and responsibilities must be well defined. In addition, the respective responsibilities and authority of each PD/PI must be specified. The application must ensure that a multidisciplinary team of appropriate personnel (clinician, statistician, data manager, study coordinator(s), etc.) are proposed to facilitate the implementation of all aspects of the clinical trial, including recruitment of subjects, design/implementation of the clinical protocol, and coordination of roles/responsibilities.

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

Provide detailed, annual budgets that will enable the trial to meet its milestones. In the budget justification, provide the detailed budget needs (per year and total) and an implementation and cost management plan (e.g., capitation).

The amount, type, and source of funding/contributions from sources other than NIH must be presented in detail in the budget justification. Third Party support of the proposed research activity (if approved) will be incorporated as a Term and Condition of Award. If the Third Party support ceases and the trial is no longer tenable without the Third Party support, a close-out plan may be requested.

Include budget support, if needed, for any personnel to attend steering committee/executive committee meetings. 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.

If applicable, budgets should include all costs associated with Data Safety and Monitoring Board (DSMB) activities, including preparing reports for the DSMB, meeting reimbursement for DSMB members, assessing DSMB member conflict, and support for at least one DSMB meeting per year. Applicants should assess the need for liability insurance for DSMB members and provide a plan commensurate with the risk of the trial. The budget should include provision for executing the plan proposed.

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.

Research Strategy: The Research Strategy must present an overview of the state of the science and relevance of the proposed clinical trial, a detailed discussion of the specific protocol, and the approach to data collection, analysis, and dissemination.

The following criteria must be addressed for both the UG3 and UH3 phase:

Significance: The significance of the proposed clinical trial and importance of the question must be clearly stated. It is particularly important that there be a discussion of how the trial will test the proposed hypotheses and why there is clinical equipoise. The application should make clear the need for and timeliness of the study with emphasis on how the results will address an evidence gap and therefore advance our knowledge of theory and practice in this area. Include a description of how results will impact clinical care to improve health. A discussion of the benefits of the study should be included for evaluation of the trial's significance.

Innovation: Explain how the proposed strategy challenges and seeks to significantly advance current research or clinical practice paradigms.

Approach: The research approach section should include a description of the supporting data and the experimental approach.

Supporting Data: Describe the formative clinical studies (including any pilot studies) that are the basis for the proposed clinical trial. Include other research as appropriate to demonstrate that the approach chosen is justified. If the clinical trial is Phase III, include relevant data used to determine that the proposed trial includes adequate numbers of subgroups of participants to allow for separate and adequately powered analyses. Conceptualization and planning must have progressed to a stage sufficient to allow for an overall assessment of the likelihood of the success of the trial.

Experimental Approach: Include critical features of conducting the clinical trial that are not already submitted as part of the PHS Human Subjects and Clinical Trials Information Form, including but not limited to, the following experimental approach items:

• A detailed description and rationale for the research hypothesis(es)
• The rationale for the specific design chosen
• Evidence supporting that: 1) equipoise exists between the arms of the trial and 2) the intervention(s) or control arm(s) tested are not known to be inferior to the range of practice (or usual care) at the sites, in their community, and described in relevant standards of care
• A detailed rationale explaining why the proposed study population is the most appropriate group to answer the research question(s)
• Justification for all assessments including clinical, laboratory, physiological, behavioral, patient-centered, or other outcomes addressing the primary and secondary research question; a description of the use of patient reported outcomes as well as non-traditional data collection approaches (e.g., telephone, mobile devices, or web-based systems)
• A description of the proposed use of available resources, as applicable
• A description of the laboratory evaluations (as appropriate) and plans to implement and monitor Good Clinical Practices (GCP), Good Laboratory Practices (GLP) and Good Manufacturing Practices (GMP), as appropriate should be provided
• A description of how stem cell or stem cell-derived product survival (short or long-term), function and integration will be monitored in vivo
• A discussion of potential challenges in implementing the research protocol and how they will be addressed
• A discussion of major challenges in implementing the study and how they will be addressed
• A discussion of event rates and contingency plans if the effect size or event rate is underestimated
• Participant follow-up procedures

Core Milestones

Propose and justify milestones that will be subject to peer-review. A milestone is defined as a scheduled event in the project timeline that signifies the completion of a major project stage or activity. Milestones must be relevant, measurable, results-focused and time-bound, and should address timing of overall recruitment/enrollment and retention goals. The milestones should address accrual goals for women, minorities, and individuals of all ages, including children and older adults, and any other identified requirements for completion of the approved research.

Describe the milestones that will be met in the UH3 phase to address the specific aims and ensure the successful completion of the clinical trial and dissemination of its results. CCC/DCC core milestones of particular interest include, but are not limited to:

Core UG3 Trial Milestones

• Complete finalized protocol and informed consent documents
• DSMB review and approval of final protocol, template consent(s) and/or assent(s), and data and safety monitoring plan
• IRB approval of final protocol and consent and/or assent
• Enrollment of the first participant during the UG3 phase
• 25% of sites activated

Core UH3 Trial Milestones

• Enrollment of 25%, 50%, 75% and 100% of the projected recruitment for all study participants, including women, minorities and individuals of all ages, including children and older adults (as appropriate)
• Study closure and completion plans
• Collection of data related to primary and secondary endpoints and database lock
• Submission of primary manuscript to peer-reviewed scientific journal(s) and dissemination of results

Letters of Support: Letters of support from clinicians or clinical department chairs whose support is necessary to the successful conduct of the trial must be provided.

Applications must include a Letter(s) of support signed by an authorized organization representative (AOR) confirming that Non-Federal sources of matching or partial funding (cash and in-kind contributions such as salary, consultant costs, equipment) are available.

The following modifications also apply:

All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan that describes how the following will be met:

• Cleaning, quality control and deidentification of individual participant-level data.
• Providing and refreshing the deidentified data to the RM Innovation Catalyst at least every six months throughout the study.
• Providing the final locked dataset to the RM Innovation Catalyst no later than six months prior to the end of the award.
• Submitting summary results to ClinicalTrials.gov within one year of the primary completion date (per regulation and NIH policy).

To be considered complete, applications must:

• Include a plan to make available representative samples of the source stem cell and clinical-grade stem cell-derived product for in-depth and independent characterization.
• Describe plans to make available data collected from long-term follow-up of study participants to the RM Innovation Catalyst.

Blank copies of the consent forms must be included in the Appendix. The consent forms must contain the appropriate information to define risks and benefits of the study.

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.

Section 2 - Study Population Characteristics

2.2 Eligibility Criteria

If applicable, include the required health status of study participants.

2.5 Recruitment and Retention Plan

The Recruitment and Retention Plan should address: 1) the expertise of the individual(s) responsible for screening, approaching, and consenting potential participants; 2) engagement of patient advocacy groups; 3) the process for identification and screening of study participants; 4) primary and back-up recruitment strategies (e.g., use of electronic health records); 5) implementation of the consent and/or assent process(es); 6) participant retention and adherence strategies; 7) possible competition from other trials for study participants; 8) engagement of the clinical community(ies) that will play a critical role in the recruitment and retention; and 9) recruitment of groups for cluster-randomized trials (if applicable).

For projects with more than one clinical site, applicants should identify one site that will serve as data coordinator for all sites. The data coordinating site (DCS) will serve all sites with a range of administrative functions, including organizing investigator and External Advisory Panel meetings, arranging conference calls, maintaining standard protocols, developing an inventory of consortium biospecimens, and designing and maintaining a website for the program. It will also coordinate cross-site training opportunities, with a focus on technical development of trainees, and implementation of common data elements to facilitate data harmonization. If multiple sites are involved, provide a table of the recruiting sites and site PD/PIs showing enrollment goals and number of potential participants available at each site.

2.7 Study Timeline

Include a table or graph of the overall study timeline. This is expected to be a visual representation (such as a Gantt Chart) of core milestones and key project management activities. A narrative is not expected in this section.

The CCC and DCC are expected to provide the same overall study timeline to reach the same major milestones. The study timeline should include core milestones that need to be met throughout the lifecycle of the clinical trial (to i nclude both the UG3 and UH3 phases) to ensure its success, and the subtasks that will be used to reach the milestones. It is expected that the overall timeline will clearly indicate which subtasks will be performed by the CCC and which subtasks will be performed by the DCC. The period of time for the study duration is expected to be displayed in months and must include, but is not limited to, the following:

(a) the study opens to enrollment
(b) core milestones (see below) are met
(c) subtasks needed to reach the core milestones
(d) when final transfer of the data to the DCC will occur
(e) analysis of the study data
(f) submission of the primary study manuscript for publication

Section 3 - Protection and Monitoring Plans

3.3 Data and Safety Monitoring Plan

In the Data and Safety Monitoring Plan, specify criteria for adverse events reporting, intervention discontinuation, and stopping guidelines. In addition, if a DSMB is used , include a plan for assessing DSMB member conflict.

3.5 Overall Structure of the Study Team

Include a description of the following:

• The role of the Executive Committee and Steering Committee as well as any internal or external advisory committees
• The oversight, responsibilities, and coordination of any sites or cores proposed
• The role of any sub-contractors or providers of services, personnel, or facilities
• The coordination between the separate components including NIH
• Key channels used to reach and inform each stakeholder group and receive feedback
• How disputes will be resolved between stakeholders

Section 4 - Protocol Synopsis

4.1 Brief Summary

Include protocol title. Summary must present the protocol that will be implemented at the site(s).

4.2 Study Design

4.2.a Narrative Study Description

Describe the intervention to be tested, the number of sites planned, and the protocol to be followed in each arm of the trial. Include a brief description of plans to standardize and optimize adherence to the protocol at the site(s). Specify concomitant interventions, if applicable. Describe the proposed experimental design including a discussion of the clinical trial design and the rationale for the particular design chosen.

4.2.c Interventions

Description. ?Describe the rationale for the choice and source of the intervention including such specific information as critical quality attributes of stem cell-derived product, dose, route of administration, period of administration, choice of formulation, device specifications, and key characteristics of other forms of proposed approaches such as diagnostic tests and interventions involving drugs, biologics, or biomaterials. Describe plans and methods for in vivo tracking and monitoring of stem cell function. Describe procedures and methods for monitoring safety. Specify criteria for intervention discontinuation and stopping guidelines.

4.4 Statistical Design and Power

The statistical plan must justify the proposed sample size based on appropriate study assumptions. Explain how the outcome(s) will address the hypothesis(es) being tested. Describe plans for interim and final analyses; methods of bias control; and methods for handling missing data (as applicable). The description should be detailed enough to allow replication of the analysis by an independent statistician.

For Phase III clinical trials, include plans for evaluation of the primary outcome(s) by race/ethnicity, sex and gender, and include all relevant data to assess whether or not the trial includes adequate numbers for valid analyses of subgroups. In addition, justify adequacy of power to analyze subgroups of participants. Adaptive designs should include a pre-specified adaptation plan that allows for clear go/no-go decisions and pre-specified analysis boundaries.

Include a description of the approach to data management and validation, including data management systems, methods of data entry and cleaning, event tracking and logistics, case report forms, and methods for monitoring the quality and consistency of the intervention(s) and data collection; policies and methods for ensuring blinding of study results ; adjudication of events (as needed); and data reports.

4.6 Will the study use an FDA-regulated intervention?

4.6.a If yes, describe the availability of Investigational Product (IP) and Investigational New Drug (IND)/Investigational Device Exemption (IDE) status:

For trials using an FDA-regulated product and requiring an IND/IDE application for authorization/approval to administer the product to humans, such authorization or approval must be secured and evidence of this authorization or approval provided before the NIH award will be made. If the protocol is exempt from an IND or IDE, applicants are required to provide a copy of the exemption letter from the FDA.

Section 5 - Other Clinical Trial-Related Attachments

5.1 Other Clinical Trial-related Attachments

Attachments listed below must be provided or the application will not be peer reviewed.

1. Clinical Trial Research Experience: Applicants must provide a detailed listing of trials that demonstrate experience in trial coordination in the last 5 years. The table must be provided as an attachment called "Clinical Trial Research Experience.pdf" and may not exceed 3 pages.

The table columns must include:

Column A: clinical trial title

Column B: applicant's role in the trial

Column C: a brief description of the trial design

Column D: planned enrollment

Column E: actual enrollment

Column F: number of sites

Column G: whether the trial(s) were completed on schedule or not

Column H: publication reference(s)

2. Project Management Plan: A Project Management Plan must be provided as an attachment called "Project Management Plan.pdf" and may not exceed 3 pages. The Project Management Plan should describe the strategy that will be used throughout the project to ensure that the unique goals of the clinical trial are met. Project management planning should directly support the needs of scientific study leadership to identify barriers, make timely responses, and optimize the allocation of limited resources to meet pre-defined study objectives. The project management plan should describe:

• The role of the project manager;
• The project's critical path to meet scientific objectives within budgetary limits;
• The contingency plans in the event that there is inadequate progress toward achieving milestones;
• Business roles, executive decision-making, and accountability standards;
• Key methodology and standard operating procedures governing resource management, study deployment, operations/execution, and study closure;
• How the project management team will resolve fiscal and logistical issues in a timely manner, including plans to pro-actively evaluate and prioritize study risks and issue corrective responses;
• Processes required for orderly project closure including how data and specimens will be handled.

In summary, the project management plan must provide sufficient detail to demonstrate the ability to achieve the goals of the clinical trial on-budget and on-time and to successfully manage and mitigate risks.

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.

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 16, 2019.

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 16, 2019.

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.

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

Significance

Does the project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

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

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 survival, function and integration, mechanism of action , or effectiveness)?

Investigator(s)

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?

Specific to this FOA:

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

Innovation

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

Specific to this FOA:

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

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed project ? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and 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?

Specific to this FOA:

• How strong is the plan to make available representative samples of the source stem cell and clinical-grade stem cell-derived product for in-depth and independent characterization?
• How strong are the plans to make available data collected from long-term follow-up of study participants to the RM Innovation Catalyst?

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?

Does the application adequately address the following (if applicable):

Study Design

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

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

Are the methods and timelines for post-treatment monitoring and evaluation of study participants adequate to fully ascertain the effects of the treatment? Are the plans to standardize, assure quality of, and monitor adherence to, the trial protocol and data collection or distribution guidelines appropriate? Is there a plan to obtain required study agent(s)? Does the application propose to use existing available resources, as applicable?

Data Management and Statistical Analysis

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

What strengths and weaknesses are there in the study design? How strong is the evidence for equipoise? How well does the Clinical Protocol Synopsis attachment describe the necessary elements of the clinical trial, and how likely is it that the protocol can be efficiently implemented at each site? How strong is the discussion of event rates, and are these realistic? How effectively does the Project Management Plan identify and describe risks to implementation, and how well are contingency plans described?

Is there evidence of the ability of the individual site to (1) enroll the proposed numbers, (2) adhere to the protocol, (3) collect and transmit data in an accurate and timely fashion, and (4) operate within the proposed organizational structure?

If the clinical trial is Phase III, does the application include all relevant data to assess whether or not the trial should include adequate numbers of subgroups of participants to allow for separate and adequately powered analyses?

Specific to this FOA:

Environment

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

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

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

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

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

Study Timeline

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

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

Milestones

How strongly do the milestones address the specific aims of each phase? Are the listed milestones for each phase appropriate for the goals of the project? To what extent are the milestones relevant, measurable, achievable, result-focused and time-bound? How strong are the proposed contingency plans in the event that there is inadequate progress towards achieving the UG3 and/or UH3 milestones?

Data and Safety Monitoring

Is the proposed Data and Safety Monitoring Plan appropriate for the proposed clinical trial? What is the quality of the DSM Plan to monitor the site and participating facilities (e.g., labs, pharmacies)?

Do the consent forms contain the appropriate information to communicate risks and benefits of the study and address the data sharing plan?

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

Not Applicable

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).

In particular, reviewers will comment on the following:

• Data Sharing Plan that describes how the following requirements will be met:

- Cleaning, quality control and deidentification of individual participant-level data.

- Providing and refreshing the deidentified data to the RM Innovation Catalyst at least every six months throughout the study.

- Providing the final locked dataset to the RM Innovation Catalyst no later than six months prior to the end of the award.

- Submitting summary results to ClinicalTrials.gov within one year of the primary completion date (per regulation and NIH policy).

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 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.

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

Applications will be assigned on the basis of established PHS referral guidelines to the NHLBI. 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 Heart Lung Blood Advisory Council. The following will be considered in making funding decisions:

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

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.

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

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

Institutional Review Board or Independent Ethics Committee Approval: Grantee institutions must ensure that all protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the awardee must provide NIH copies of documents related to all major changes in the status of ongoing protocols.

Data and Safety Monitoring Requirements: The NIH policy for data and safety monitoring requires oversight and monitoring of all NIH-conducted or -supported human biomedical and behavioral intervention studies (clinical trials) to ensure the safety of participants and the validity and integrity of the data. Further information concerning these requirements is found at http://grants.nih.gov/grants/policy/hs/data_safety.htm and in the application instructions (SF424 (R&R) and PHS 398).

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

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.

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 awardee PD/PI will have primary and lead responsibilities for the project as a whole, including research design and protocol development, participant recruitment and follow-up, data collection, quality control, interim data and safety monitoring, final data analysis and interpretation, preparation of publications, as well as collaborations with other awardees.

Upon completion of the project, awardees are expected to put their data into the public domain and/or make them available to other investigators, according to the approved plan for making data and materials available to the scientific community.

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

The NIH Project Scientist will assist with development of research protocols, monitor patient recruitment and study progress, ensure disclosure of conflicts of interest, and ensure adherence to NIH policies.

The NIH Project Scientist will serve on the Steering Committee and other study committees, when appropriate, as a non-voting member. The NIH Project Scientist may work with awardees on issues coming before the Steering Committee such as recruitment, protocol development, follow-up, quality control, adherence to protocol, possible changes to the protocol, interim data and safety monitoring, final data analysis and interpretation, preparation of publications, and development of solutions to major problems such as insufficient participant enrollment.

In addition to the Project Scientist, a separate 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.

An independent Data and Safety Monitoring Board (DSMB) will be established to oversee participant safety in the clinical trial and provide overall monitoring of interim data and safety issues. As part of the collaborative activities under this cooperative agreement, the NIH will collaborate with the awardees to appoint and/or agree upon a single DSMB for monitoring the clinical trial. The DSMB may be appointed by the NIH, or with the approval of NIH, the DSMB could be an institutional DSMB. At the first meeting in the UG3 phase, the DSMB will review the awardee's protocol and potentially recommend modifications. Subsequently, the DSMB will monitor and review recruitment, adverse events, data quality, outcome data, and overall awardee performance. The DSMB has the responsibility to review interim data and final data, and recommend whether the protocol should be modified, and, at each meeting, whether the study should be continued or should be terminated early. An NIH scientist other than the NIH Program Official or Project Scientist will serve as Executive Secretary to the Board. Because the DSMB serves as an independent advisory group to the NIH, study investigators shall not communicate with DSMB members regarding study issues, except as authorized by the Board's Executive Secretary.

NIH will conduct at least two administrative reviews to determine progress toward achievement of milestones included in the mutually-agreed upon milestone plan, one towards the end of the UG3 phase, and one within the first two years of the trial UH3 phase. If the trial milestones have not been satisfactorily met, subsequent funding years may not be approved.

The NIH reserves the right to phase-out or curtail the study (or an individual award) in the event of (a) failure to develop or implement a mutually agreeable protocol, (b) substantial shortfall in subject recruitment milestones, core milestones mutually agreed upon by the recipient organization and PD/PI and the NIH, consortium participation and collaboration with other awardees, (c) substantive changes in the agreed-upon methodologies and tools with which NIH cannot concur, (d) human subject ethical issues that may dictate a premature termination, or (e) results that substantially diminish the scientific value of study continuation.

Areas of Joint Responsibility include:

Award continuation, even during the period recommended for support, is conditional upon satisfactory progress. If, at any time, recruitment, falls significantly below projections, or milestones mutually agreed upon by the recipient organization and PD/PI and the NIH are not met, the NIH may consider ending support and negotiating an orderly phase-out of the award. NIH Grants Management and Program Officers will closely monitor progress at all trial stages including milestones, accrual, and safety.

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 and clinical-grade stem cell-derived 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) and that 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. Awardee PD/PI and NIH Project Scientist will establish a timeline for sharing cell characterization and clinical outcome data. 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 disagreement 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 will be convened. It will have three members: a designee selected by the Executive Committee (with the NIH member absent from the discussion) or by the individual awardee in the event of an individual disagreement, a second member selected by NIH, and the third designee with expertise in the relevant area selected by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution does not alter the awardees' right to appeal an adverse action that is otherwise appealable in accordance with PHS regulations at 42 CFR part 50, subpart D and HHS regulation at 45 CFR part 16.

Matching:

Matching funds (at least a 1 to 1 match) will be required (as per the 21st Century Cures Act) for the specific project awarded in each budget period. 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 awardee agrees that if matching funds become unavailable and replacement matching is not secured within 90 days of funds 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 of a new matching agreement. Awardee agrees to notify NIH within 10 days of matching funds becoming unavailable. 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 Grants Policy Statement.

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]

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]

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]

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]

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]

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

Gloria Velez
National Center for Advancing Translational Sciences (NCATS)
Telephone: 301-435-0875
Email: [email protected]

Section VIII. Other Information