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

Catalyze Product Definition: Small Molecules and Biologics

The NHLBI Catalyze innovation program is designed to provide a suite of comprehensive support and services to facilitate the transition of basic science discoveries into new treatments for diseases and disorders that fall under the NHLBI mission. The Catalyze Program initiatives support product development (supporting product definition studies and pre-clinical research and development) and enabling technologies and transformative platforms. Catalyze is coordinated by the Catalyze Coordinating Center, which provides program administration and evaluation, milestone-driven project management, communications and outreach, as well as development guidance for projects in the Catalyze portfolio. The Catalyze program aims to create cultural and systemic changes to more rapidly move breakthrough innovations to products that will have health, economic, and societal impact. Information on the Catalyze programs can be found on the Catalyze website.

This specific Catalyze Product Definition initiative will provide the early stage translational support needed for the activities required to develop potential therapeutic candidates to treat HLBS diseases and disorders. This FOA is intended to provide support for early stage projects through use of a bi-phasic approach. The R61 phase allows investigators to identify, validate and screen compounds of interest and the R33 phase supports identification of a lead series for pre-clinical testing and development. A companion FOA (RFA-HL-20-027) is available for more advanced projects that have already completed the activities supported by the R61 phase of this initiative, but need continued support to identify a lead series. Through Catalyze, the small molecule and biologics initiatives have companion initiatives that support development of devices and diagnostics (RFA-HL-20-024 and RFA-HL-20-028). See website for additional information.

It is anticipated that projects supported by this FOA will provide a robust data set that can be used to pursue further NIH or other private funding for preclinical optimization and development of therapeutic candidates.

Objectives

1. Novelty: This FOA seeks applications that propose to apply new knowledge around novel targets, mechanisms and pathways. Projects should aim to develop therapeutics that are significant improvements over existing therapeutics for HLBS diseases and disorders. It is expected that the proposed projects will aim to identify and validate disease targets, compound library screening and hit development, develop assays to test binding affinity, that are significant improvements over existing screening methods and should provide evidence of the unmet gaps and needs to support proposed activities.
2. Biological rationale and preliminary data: This FOA will fund projects that have a strong biological rationale for the intended approach, which have preliminary data that reflect well-designed experiments (either from the literature, data from other sources, or, when available, from investigator-generated data).
3. Relevance for therapy development: Projects that propose to develop novel therapeutic agents that can be advanced towards development of NHLBI mission-relevant therapies and cures and fulfill the clinical gaps and needs are of high programmatic interest.

Phased Award Activities

The purpose of the R61 phase is to identify, validate and screen therapeutic compounds of interest.

Examples of activities for R61 phase include, but are not limited to:

• Synthesis of the novel therapeutic agent(s) to support proposed activities.

• Synthesis of novel molecular imaging agents for imaging, therapy monitoring, and risk stratification.

• Development and validation of assay(s) (including phenotypic assays) to support a succinct testing funnel, including for example, assays to measure specificity, potency, stability to protease and/or other metabolic enzymes, and cellular uptake.

• Development of in vitro assays or ex vivo potency/efficacy studies designed to indicate the specific ability of an agent to achieve a desired biological effect.

• Structure activity relationship studies.

• Development of assays to evaluate cellular uptake, engagement, infection, aggregation, downstream functional measures in vitro or ex vivo, purity and specificity. Assays to measure DNA, RNA, and protein levels of either endogenous genes or delivered products, downstream in vitro or ex vivo functional read-outs, viral titer, viral particle load stability and specificity.

• Development of assays to evaluate purity and identity of the therapeutic by surface markers or specific proteins, morphological measures, differentiation, functional measures in vitro or ex vivo, stability and immunogenicity.

• Assay development and optimization for low-throughput or high-throughput screening.

• A combination of assays may be developed to demonstrate relevant biological activity when a single assay may not provide adequate measurement of overall potency due to a complex mechanism of action or multiple activities of a preliminary therapeutic agent.

• Initial survey of patent literature followed by inventions disclosures and patent filing.

The purpose of the R33 phase is to identify promising lead compounds for pre-clinical testing and development.

Examples of activities for the R33 phase include, but are not limited to:

• Synthesis and characterization of select library of therapeutic agents or molecular imaging agents.

• Development and selection of cell lines/vectors to produce bioactive agents with acceptable potency and stability, cellular uptake/engagement, or secondary in vitro functional assays.

• Assessment of therapeutic candidate's properties using computational analysis and early physicochemical measurements, solubility, cell permeability and efflux.

• Assessment of initial pharmacokinetic parameters such as absorption, distribution, metabolism, and excretion (ADME) in animal models.

• Assessment of potential off target activities.

• Physico-chemical and biological characterization of therapeutic agent(s). This could include for example, confirmation of purity, stability, absorption, distribution, metabolism, and excretion pharmacokinetics and pharmacodynamic studies.

• For gene and cell therapy, these include characterization of gene copy numbers or tropism in tissues or cell engraftment.

• Validation and replication studies to confirm observed results.

Examples of activities that are not appropriate for and would be considered non-responsive to this FOA include, but are not limited to:

• Development of assays or probes to support basic understanding of disease or other basic research.

• Development of devices or diagnostics (See companion FOAs RFA-HL-20-024 and RFA-HL-20-028).

• Development of risk, detection, diagnostic, prognostic, predictive, and prevention biomarkers.

• Investigational New Drug (IND) enabling studies.

• Manufacture of therapeutic agents under good manufacturing practice for clinical use.

• Clinical research and clinical trials.

Special Requirements for this FOA

The NHLBI recognizes that early stage therapeutics development requires access to unique expertise, including regulatory, reimbursement, business, legal, partner engagement, and project management. The NHLBI will work with awardees to provide guidance and support in these unique areas of expertise, if needed, to enable advancement of therapeutic agents toward preclinical testing and development.

Project Management

Each project should use project management processes that enable continuous assessment of the progress of the studies relative to established milestones in order to make strategic decisions regarding each project. Project management may be at the local level, or in some instances provided through NIH support.

R33 Phase Special Requirements

Cost Matching Component

Cost matching is required for the R33 Phase (Phase II) only. The R33 Phase of this FOA requires a minimum of a 0.25:1 non-Federal cash match of the Federal direct costs requested for the R33. The awardee will be expected to provide evidence of matching funds to NIH in the form of a letter of support prior to the meeting of the NHLBI committee that will make the decisions regarding whether an awardee will transition from the R61 to the R33 award. Proof of matching funds is not required at the time of application. However, to be considered responsive to this FOA, applicants are expected to include a description in the Budget Justification of how the matching funds will be used. Evidence of the cash match is required prior to release of R33 Federal funds. The cash match must be reported annually to the NIH. In-kind contributions are encouraged, but do not apply to the cash matching requirements and do not need to be reported to the NIH. Institutions must be able to document their actual 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. The cost matching requirement of the R33 award is not negotiable. 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

Accelerator Partner(s)

At least one Accelerator Partner is required for the R33 portion of this award. The support of an Accelerator Partner is expected to help advance the proposed project to a stage suitable to continue product development in the private sector or apply for support through the NHLBI Catalyze Preclinical or other translational programs. Developing therapeutics requires a multidisciplinary approach, and it is expected that applicants will consider how they will identify and foster relationships with potential licensing and commercialization partners early in the therapy development process once an award is made. Collaborative relationships with ecosystem partners knowledgeable in the therapeutic development process (such as those from biotechnology or pharmaceutical companies) as well as those familiar with what the desired end product should look like (such as clinicians and biostatisticians), result in vested shared interests, and access to complementary development expertise and resources for successful development. The Accelerator Partner should catalyze professional development by providing innovators with skills development and mentoring to enable them to assess the medical and commercial potential of their research by bringing together experienced entrepreneurs and scientists and by providing connections between the businesses, industries, sources of private capital, and research performing institutions. Accelerator partners are encouraged to provide access to expertise and mentoring related to: product development stages, business development and commercialization strategy, market analysis, preparation of regulatory submissions, intellectual property protection, and reimbursement strategy. Career development through Accelerator Partners is highly encouraged to achieve the goal of exposing awardees to the myriad processes required to translate discoveries into therapies. It is expected that awardees will search for a Accelerator Partner early in the R61 phase of award.

It is acceptable for an Accelerator partner to provide the matching funds for the R33 stage, but not required. It is anticipated that the Accelerator Partner will support activities required for lead compound identification, by providing innovator skills development and mentoring, and providing appropriate development expertise.

Milestones

This Catalyze Product Definition Small Molecules and Biologics initiative is a R61/R33 phased innovation award. The R61 phase of this program will allow investigators to identify, validate and screen compounds of interest and the R33 phase supports identification of the most promising lead compounds for preclinical testing and development. To be responsive to this FOA, applicants must propose two separate groups of clear, quantifiable milestones with timelines (for R61 and R33 phases) to be completed sequentially within a three-year period, but with no more than two years in either stage. Although milestones for the R61 and R33 activities must be submitted at the time of application and will be reviewed simultaneously, funding for the R33 component is contingent on achieving pre-specified milestones during the R61 component. Completion of milestones will ensure sufficient progress during the R61 to provide feasibility and scientific rationale for the conduct of product definition activities proposed in the R33.

Milestones are goals that are quantifiable for measuring success, may be used for go/no-go decision making and should include associated timelines and quantitative criteria. All milestones should be useful as a measure of progress toward the overall goal of the project. Specific Aims or a list of activities planned for each year are not considered milestones because they do not provide decision-making goals. Milestones must be identified in the application, and these may be negotiated by the NHLBI team pre-award, based on comments of the peer review panel. NHLBI emphasizes the importance of the robustness and reproducibility of experimental results in evaluating progress. At the end of the R61 phase, investigators must exhibit successful completion of target identification and identification of lead compounds, and the R33 phase should result in in vitro and preliminary in vivo efficacy studies and identification of lead compounds. Lead optimization may be part of the R33 phase.

Transition to the R33 Phase of Award

Transition from R61 to R33 will be contingent on (1) acceptable progress and achievement of milestones as described above, (2) providing evidence of meeting the 0.25:1 non-Federal cash matching requirement and (3) securing an Accelerator Partner. Evidence of having secured the cost matching requirement and the Accelerator Partner is not required at the time of application, but will be needed at the time of R61 milestone review to assess transition to the R33 phase of award.

Intellectual Property and Regulatory Considerations

Projects at the stage of development supported by this FOA may already be or will be developed to the point where IP and regulatory strategies should be under consideration or already developed. Continued development of IP and regulatory strategies will be required for transition from the R61 phase to the R33 phase of the award. See Section IV, Application and Submission Information, SF424(R&R) Other Project Information for details.

Additional Considerations

Applicants are strongly encouraged to contact Scientific/Research Staff listed in Section VII to discuss potential research projects prior to submitting an application.

Prior to funding an application, NHLBI Program staff may contact the applicant to discuss the proposed milestones and any changes suggested by the NHLBI review panel or Program staff. A final set of approved milestones will be specified in the Notice of Award.

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 Sharing

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.

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
National Heart, Lung, and Blood Institute
Email: [email protected]

IP and Regulatory Strategies (Required)

The filename "IP and Regulatory Strategies.pdf" should be used and attached.

NHLBI recognizes that applications submitted in response to this FOA may detail projects at different stages of development. Applications should include a detailed description of Intellectual property (IP) and regulatory strategies for more advanced projects. If the project is too early for a well-defined strategy, the applicant should indicate so and provide a brief description of the current stage and potential IP and regulatory strategies. For more advanced projects, applicants should address their current understanding of regulatory and IP requirements for the proposed product, even if the plans are not fully complete.

For IP, describe any known constraints that could impede the therapeutic discovery and development (e.g., certain restrictions under transfer or sharing agreements, applicants' previous or present IP filings and publications, similar therapies that are under patent protection and/or on the market, etc.) and how these issues could be addressed with achieving the goals of this program. If any third-party IP is required, identify whether there are any limitations on its use and include a letter from the third-party appended as part of this attachment. If patents pertinent to the therapy being developed under this application have been filed, indicate the details of filing dates, what type of patents are filed, application status, and associated USPTO links, if applicable. Describe plans for working closely with institutional technology transfer officials to ensure that royalty agreements, patent filings, and all other necessary IP arrangements are completed in a timely manner and that commercialization plans are developed and updated over the course of the project. Applicants are strongly encouraged to prepare the IP section of this application in consultation with their institution's technology transfer officials.

For the regulatory path, describe the steps that will be taken to refine and align the proposed project with regulatory requirements either during the currently requested award period or in the future. If the project as proposed is too early to have a regulatory strategy, indicate so in the application and provide a brief description of 1) why the R61 phase is too early for description of a regulatory plan and 2) how they will develop a regulatory plan in advance of requesting transition to the R33 phase of the award. If a drug or biologic is being developed, describe the data to be collected during the project period to support an Investigational New Drug filing. If the development team has already interacted with their local IRB or FDA regarding regulatory oversight of their proposed product, provide evidence of prior communications (letters/emails) appended as part of this attachment. If the project involves re-purposing of a therapy currently under development in the US, a letter of support for the new indication from the manufacturer of the therapy confirming access to sufficient quantity of the not-yet-marketed technology to perform the proposed research program must be submitted as post-submission material. Describe the expected regulatory pathway and describe any foreseeable regulatory risks or accelerated programs that could impact development.

IP and regulatory strategies are required and will be criteria considered for the transition from the R61 to the R33 phase of the award.

Applicants are also strongly encouraged to contact the appropriate NIH Scientific/Research contact listed in Section VII or NHLBI’s Office of Translational Alliances and Coordination for questions regarding application expectations for IP and regulatory prior to submission.

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

Applicants must include budget support for the PD/PI to participate in a 1.5-day NHLBI-held innovation meeting or workshop once each budget year in the Washington, DC/Metropolitan area.

Applicants should budget for an appropriate amount of project management support.

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 program is no longer tenable without the Third Party support, a close-out plan may be requested.

Cost Matching

The evidence of matching funds is not required as part of this application however submitted budgets must clearly document the total costs and the source and amount of matching funds, as well as the Federal and Institutional (non-Federal) components of the budget in the budget justification.

Budget Justification: A total project budget justification (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. Although the budget submitted at the time of application should document use of non-Federal funds, the evidence of matching funds will not be required until the NIH awardee submits the materials required by the NHLBI committee that will evaluate progress and determine whether the awardee has successfully met milestones and additional R33 entry requirements (cash match and accelerator partner) for successful transition from the R61 to the R33 award. All costs and contributions used to satisfy the matching requirement must be documented by the recipient prior to release of the R33 award, and are subject to audit.

Specific Aims: Within the Specific Aims section, include headers titled R61 Phase Specific Aims and R33 Phase Specific Aims. Under each header, state the specific objectives of the efforts, including the activities to be conducted to meet the goals of each phase. The goal of the R61 phase of this FOA is the target identification and validation, and the goal of the R33 is lead series identification.

Research Strategy: Describe both the R61 phase and the R33 phases of the proposed project. Include a background section that clearly outlines the biological and therapeutic rationale for the application, including: (1) a description of the relationship between the proposed therapeutic target and the disease of interest, (2) evidence for unmet medical need in the therapeutic disease area, (3) a brief description of any pertinent history for therapeutic development in the disease area, (4) evidence supporting the novelty of the therapeutic approach, and (5) a summary of the project status, including information regarding therapeutic agents to be tested in the current application. The description of the R61 phase should include a carefully designed plan for identifying and characterizing the proposed preliminary therapeutic agents from a physicochemical, biophysical, and biological perspective. Provide a a carefully developed rationale for the experimental design and a description of how data obtained in the R33 phase will provide a path for optimization of preliminary therapeutic agents. Include a description of how the expertise of a potential Accelerator Partner might fill anticipated gaps in development as related to the project goals.

Describe how knowledge gained from this work will support future therapeutic discovery efforts. For example, an outline of activities and criteria for advancement from hit identification to lead optimization and candidate identification would be appropriate for both small molecule and biologic preliminary therapeutics.

Milestones

Define milestones for both the R61 and the R33 phases of the grant. Milestones must be relevant, measurable, feasible, scientifically justified, results-focused and time-bound. Transition from the R61 to the R33 phase is contingent upon the successful completion of proposed R61 milestones, thus, the description of the milestones that need to be met during the R61 phase to allow for successful initiation of the R33 phase must be clear. The milestone plan also needs to describe the milestones that need to be reached in the R33 phase to address the specific aims and ensure the successful completion of the entire project.

Milestones should provide clear indicators of a project's continued success or emergent difficulties.

Timeline

Provide a timeline with milestones that establish specific goals for progression from the R61 phase to the R33 phase. Indicate when it is anticipated that essential components of the project will be completed. The proposed timeline with specific milestones must be clearly delineated and should appear as the last element of the Research Strategy section.

Project Management

Describe plans for utilizing project management processes to enable continuous assessment of the progress of the project relative to the established milestones and how the progress assessments will be used to make strategic decisions regarding the proposed project. Project management may be at the local level, or in some instances provided through NIH support. Describe plans f for how the selected project management process(es) will support identification, validation, and lead series selection studies.

High-quality and reproducible product definition studies are an essential cornerstone of the translational research enterprise. Attention to principles of study design and transparency is essential to enable stakeholders to assess the quality of the experimental design and scientific findings. In support of this important goal, investigators must follow instructions to address Rigor and Reproducibility (https://grants.nih.gov/policy/reproducibility/index.htm).

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.

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

Study Record: PHS Human Subjects and Clinical Trials Information

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

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

Not applicable

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 NHLBI. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

If the project involves re-purposing of a therapy currently marketed in the US, a letter of support for the new indication from a manufacturer of the therapy may be submitted as post-submission material.

If the project involves re-purposing of a therapy currently under development in the US, a letter of support for the new indication from the manufacturer of the therapy confirming access to sufficient quantity of the not-yet-marketed technology to perform the proposed research program must be submitted as post-submission material.

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.

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?

Specific to this FOA:

How well does the application describe how the project will provide significant improvement over the existing technology? To what extent is the project relevant for therapeutic development, and what is the strong rationale for the proposed activities? How will the project, if successful, bring the investigators closer to a therapeutic that will be a significant improvement over existing therapeutics to treat HLBS disorders?

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:

What makes the investigators knowledgeable and experienced about the biological target area? To what extent does the researcher have experience with target identification and validation, and lead selection, or include collaborators with the appropriate expertise to support the proposed experimental design and implementation activities and overall project?

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:

To what extent is the project novel for therapeutic development?

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:

To what extent has the innovator identified clear, well-defined, measurable goals to pursue identification, validation of novel targets, mechanisms and pathways? What are the clear, well-defined, measurable goals to pursue lead series selection?

To what extent is the project feasible? How will the project, if successful, produce a well-validated assay that can support future therapeutic development for HLBS diseases and disorders? How feasible is the timeline for the work proposed? To what extent is the process for identifying and validating targets appropriate? How appropriate is the process for characterizing and selecting compounds? To what extent is the plan for therapeutic candidate discovery reasonable? To what extent will the project produce therapeutic candidates that meet the entry criteria for Catalyze Preclinical or other federal or private further development mechanisms?

In what ways have the investigators considered the rigor of their experimental design? To what extent does the proposed project use sufficient experimental and statistical rigor? For key experiments, how adequately does the application explain assumptions for power analysis, describe statistical analysis methods and criteria for data inclusion or exclusion, and detail the procedures of how blinding and randomization will be conducted?

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?

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?

Review Criteria for Project Management

To what extent is the described project management structure likely to be efficient and effective in keeping the activities on schedule according to the proposed timeline?

Review Criteria for Milestones and Timelines:

Are the listed milestones for each phase appropriate for achieving the goals the project? To what extent are the milestones relevant, measurable, achievable, result-focused and time-bound?

Does the set of milestones allow the evaluation of progress in the R61 phase and how will successful completion of these milestones provide confidence that the investigator will be able to successfully implement the R33 phase?

Are the timelines proposed for achieving the milestones realistic and inclusive of necessary steps, but also efficient without unnecessary steps? Are there additional key experiments that need to have milestones designated and what are they?

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

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

Renewals

Not Applicable

Revisions

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

Intellectual Property and Regulatory Strategy

How appropriate are the strategies for the stage of IP development? For IP, did the applicant adequately consider known constraints that could impede their therapeutic discovery or development and did they offer viable solutions to address these issues? If any third-party IP is required, did the applicant adequately describe whether there are any limitations that exist on its use and did the application include letter from the third-party, if relevant ?

How adequate is the description of regulatory considerations for gaining market access of their technology? Do they understand which (if any) Food and Drug Administration (FDA) Center and Review Division will review their technology? Have they proposed a market access pathway (IND leading to BLA, NDA, or 510(b)(2) application for drugs/biologics)? If they have mentioned any of the above, what is the basis of their application - personal experience, discussion with a consultant, interaction with FDA?

Applications from Foreign Organizations

Not Applicable

Select Agent Research

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

Resource Sharing Plans

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

Authentication of Key Biological and/or Chemical Resources:

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

Budget and Period of Support

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

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by a special emphasis panel convened by the National Heart Lung and Blood Institute in accordance with NIH peer review policy and procedures using the stated review criteria.

• 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.

• 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.

3. Anticipated Announcement and Award Dates

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

Section VI. Award Administration Information

1. Award Notices

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

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

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

2. Administrative and National Policy Requirements

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

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

For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/index.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-individuals/section-1557/index.htmlhttps://www.hhs.gov/civil-rights/for-providers/laws-regulations-guidance/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see https://www.hhs.gov/civil-rights/for-individuals/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

3. Reporting

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]

General Questions
Kathleen Rousche, Ph.D.
Telephone: 301-827-7981
Email: [email protected]

Product Definition - Small molecules and Biologics
Narasimhan Danthi, Ph.D.
Telephone: 301-451-5170
Email: [email protected]

Product Definition - Small molecules and Biologics
Marc Charette, Ph.D.
Telephone: 301-435-0560
Email: [email protected]

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

John Diggs
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-827-8028
mail: diggsjw@nhlbi.nih.gov

Section VIII. Other Information