Participating Organization(s)	National Institutes of Health (NIH)
Components of Participating Organizations	National Heart, Lung, and Blood Institute (NHLBI)
Funding Opportunity Title	Centers for Advanced Diagnostics and Experimental Therapeutics in Lung Diseases Stage II (CADET II)(UH2/UH3)
Activity Code	UH2/UH3 Phase Innovation Awards Cooperative Agreement
Announcement Type	New
Related Notices	October 18, 2013 - See Notice NOT-OD-14-003. Guidance on Resumption of NIH Extramural Activities Following the Recent Lapse in Appropriations. September 13, 2013 - See Notice NOT-HL-13-196. Notice of Clarification, Frequently Asked Questions, and Recorded Presentation. August 22, 2013 - See Notice NOT-HL-13-192. Notice of Change to Part 2., Section III.1 Foreign Institutions. August 21, 2013: Removed reference to ASSIST in section IV.3, since ASSIST is currently only available for multi-project applications.
Funding Opportunity Announcement (FOA) Number	RFA-HL-14-001
Companion Funding Opportunity	None
Number of Applications	See Section III. 3. Additional Information on Eligibility.
Catalog of Federal Domestic Assistance (CFDA) Number(s)	93.838, 93.839
Funding Opportunity Purpose	The purpose of this Funding Opportunity Announcement (FOA) is to invite applications for Centers for Advanced Diagnostics and Experimental Therapeutics in Lung Diseases Stage II (CADET II). The goal of the CADET program is to accelerate the development of novel products for the treatment of lung diseases and sleep disordered breathing using strategies based on relevant pathobiologic processes. Whereas the prior funding opportunity, CADET I, provided the opportunity to explore and validate potential therapeutic targets, the current funding opportunity, CADET II, hereafter designated "CADET," will support preclinical research on therapeutic products for which the target has been validated. It is anticipated that CADET projects may vary substantially in their objectives and scope of research. CADET applications must describe research that contributes to the development of a therapeutic product that modulates a validated target of clinical significance in lung disease or sleep disordered breathing. Applications may include concurrent development of a diagnostic test(s) designed to assess a pathobiologic process associated with the therapeutic target. Applications must propose two separate groups of activities to be completed sequentially in the first two years (the UH2 component) and the final 3 years (the UH3 component) of funding. Although applications for the UH2 and UH3 activities must be submitted and will be reviewed simultaneously, funding for the UH3 component is contingent on achieving pre-specified milestones during the UH2 component. These milestones will ensure sufficient progress during the UH2 to provide feasibility and scientific rationale for the conduct of research proposed in the UH3. Milestones must be identified in the application, and these may be negotiated based on comments of the peer review panel. Applicants should consult with their institution's legal authorities to plan for how intellectual property resulting from the research will be protected.

Posted Date	July 17, 2013
Open Date (Earliest Submission Date)	September 17, 2013
Letter of Intent Due Date(s)	September 17, 2013
Application Due Date(s)	(Extended to November 1, 2013 per NOT-OD-14-003)October 17, 2013, by 5:00 PM local time of applicant organization. Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.
AIDS Application Due Date(s)	Not Applicable
Scientific Merit Review	February/March 2014
Advisory Council Review	May 2014
Earliest Start Date	July 1, 2014
Expiration Date	(Extended to November 2, 2013 per NOT-OD-14-003)October 18, 2013
Due Dates for E.O. 12372	Not Applicable

Required Application Instructions

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

Part 1. Overview Information
Part 2. Full Text of the Announcement
Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

Advances in understanding of the biology of pulmonary diseases and sleep disordered breathing have generated enormous potential for the development of new diagnostic and therapeutic products that can improve patient care. The purpose of this funding opportunity is to promote the development of new therapeutic products for the management of lung diseases and sleep disordered breathing that is based on pathobiologic research. This funding opportunity will provide support and resources needed to facilitate preclinical product development, with the intent of enabling improvements in clinical care based on scientific understanding of disease mechanisms.

CADET will provide grant support for research that is needed to develop specific products for use in treating diseases of the lung or sleep disordered breathing. The NHLBI does not support projects primarily focused on malignancy-related research, vaccine development, or pathogens per se. Therefore, applicants are strongly encouraged to contact the NHLBI before submitting an application to determine its appropriateness for this FOA. In this context, "product" refers to a substance intended to be used for therapeutic purposes, such as a drug or biologic, but not a device or test/assay. All proposed studies must lead toward US regulatory approval of a specific therapeutic product. This program targets that portion of drug development between target validation and Investigational New Drug (IND) filing. "Target validation" refers to the identification and demonstration that a target has a sufficient role in disease biology to impact a clinically detectable and significant aspect of the disease. Targets may include but are not limited to specific biologic molecules or a part of a molecule (e.g., a receptor), a pathway or system, or a biologic process. Although limited target validation studies may be proposed in CADET, it is anticipated that competitive applications will involve a precisely defined target that was previously validated.

Research activities that are often required in the interval of product development between target validation and IND filing and may be appropriate for CADET support include the following:

• Identify compounds that modulate a validated target and assess their pre-clinical proof of principle and efficacy.
• Evaluate the selectivity, functionality, and "drugability" of compounds that modulate the target to select a lead candidate.
• Determine the absorption, metabolism, distribution, and elimination of a lead candidate.
• Perform toxicology and bioavailability studies in an animal model.
• Manufacture and scale up production of a lead candidate.
• Pre-formulation.
• Develop and validate concomitant diagnostic tests.

The use of CADET resources is limited to activities that are IND enabling. Hence, in addition to describing the specific studies to be completed with CADET resources, CADET applications must describe an overall product development plan that will lead to IND filing. The plan should begin with scientific identification of a pathobiologic process and end with IND filing. The plan must be summarized using a timeline in the grant application. The timeline should identify the specific studies proposed for support in CADET, noting that the cumulative data collected by the conclusion of CADET may not be sufficient for an IND without additional research. Nevertheless, the application must include a clear rationale for how the research proposed to be conducted in CADET will enable IND filing for the therapeutic product. The UH2/UH3 activity code is used to allow a stepwise progression of the development of a proposed therapeutic product. Funding of the UH3 component is contingent upon the successful completion of UH2 aims and specific, agreed upon activities and milestones, as determined by NHLBI with the recommendations of the External Advisory Board (EAB) prior to the UH3 award. For example, studies of absorption, metabolism, distribution, and elimination in the UH3 phase might be dependent on lead candidate refinement proposed for a UH2. Similarly, UH3 support for scale up production of a lead candidate might be contingent on animal toxicological studies supported with a UH2 grant. Applicants should consult with their institution's legal authorities to plan for how intellectual property resulting from the research will be protected.

CADET applications must focus on the development of a specific therapeutic product that modulates a particular target. In addition, applicants may propose concurrent activities needed to develop and validate a diagnostic test. Herein, "diagnostic test" or "diagnostic" refers to any assessment that can aid in clinical management. For example, a diagnostic test could allow selection of a patient population in which the product is expected to have more efficacious and/or less adverse effects based on pathobiologic processes. The results of the assessment may be qualitative (e.g., categories such as high and low) or quantitative with defined units of measurement. Concurrent development of a diagnostic test is optional for applications involving novel therapeutics (as defined below) but is required for any application involving products previously given an IND in the context of another disease or existing products that do not require an IND (i.e., have not been used as therapeutic agents such as a vitamin). For previously developed products, applicants must clearly describe how incorporating the use of a diagnostic test in conjunction with the product will provide a novel, biologically-based approach to management. Similar to therapeutic products, the entire diagnostic development plan does not need to be completed with CADET support. A summary of the plan for diagnostic development demonstrating an understanding of the development process, including how it will be used with the therapeutic product in clinical practice and how any needed regulatory approval will be obtained, must be included in applications with diagnostics.

Applications will be considered responsive to this FOA only if they include all of the following elements:

1. A product development plan for at least one therapeutic for use in pulmonary disease or sleep disordered breathing.

2. Proposed studies to develop a therapeutic approach that is novel and based on modulation of a target that impacts disease biology and, therefore, clinical outcome(s). To meet this requirement, either A or B and the associated subtext must be accurate:

• A) The therapeutic product itself is novel, meaning it has not been tested previously.
  • There cannot be an existing IND (for any indication).
  • The product cannot have been investigated by someone else or used widely.
• B) The product requires a new IND because:
  • The product will be used for a new indication and in a "target" patient population defined by disease biology using a diagnostic test. Using an existing drug for which an IND was previously filed and merely changing the indication (a different disease or outcome) or combining existing products is not sufficiently "novel" to be considered responsive to this FOA.

3. Planned research activities that progress beyond target validation and will enable an IND application.

4. Proposed milestones (for both the UH2 and UH3 segments of the grant period) that can be used to assess accomplishments and progress toward IND submission.

Applications will be considered non-responsive to this FOA if any of the following are included in the application:

1. Studies of combination products that include only elements of previously approved products (e.g., combining an approved drug with a device to deliver it as an aerosol).

2. Studies for changing the indication (disease) for an approved product without a novel approach to management (e.g., using a drug approved for use in COPD patients in patients with asthma).

3. Using an existing product in a sub-population of patients that is identified by an existing test (e.g., using Vitamin D in subjects who are Vitamin D deficient).

4. Clinical trials.

Development of therapeutics and diagnostics requires an especially dynamic approach to research because intermediate results may substantially alter the feasibility of subsequent studies or the relative value of alternative study designs. Therefore the CADET program is intended to allow grantees to adapt their research plans as appropriate during the project period with NHLBI oversight.

1. Grants will be awarded as Cooperative Agreements, with Terms and Conditions of Award that involve program staff of the NHLBI in the ongoing monitoring and evaluation of research activities. This arrangement will provide timely review and communication of decisions regarding modifications to research plans that are indicated by information that becomes available after the funding period begins.

2. Grants will be structured in two phases - an initial UH2 grant and a subsequent UH3 grant whose funding will be contingent on the completion of UH2 aims as determined by pre-negotiated milestones. Separation of the proposed studies into two phases is intended to encourage highly innovative and potentially high risk research. Applications must propose two separate groups of activities to be completed sequentially in the first two years (the UH2 component) and the final three years (the UH3 component) of funding.

3. NHLBI will form an External Advisory Board (EAB), including members with expertise in United States Regulations, manufacturing, toxicology, and pharmacology, to assist NHLBI staff in overall monitoring of project performance, interim data evaluation, and requests for changes in research plans. Prior to initiating the individual projects, the EAB will make recommendations to NHLBI regarding the specific research plans and associated milestones for those projects selected for funding. The EAB will also review periodic progress reports and advise the NHLBI regarding the completion of milestones and is expected to convene via regular teleconferences and up to 4 in person meetings per year in Bethesda, MD.

4. Upon request, NHLBI staff will assist CADET grantees to apply for the use of services that are provided by the following NHLBI resource organizations: Science Moving towArds Research Translation and Therapy (SMARTT) Program, NHLBI's Production Assistance for Cellular Therapies (PACT) Program, and NHLBI's Gene Therapy Resource Program (GTRP). These NHLBI resource programs have the capacity to provide the services that are necessary for preclinical drug development and may not be available at an applicant's own institution. CADET applicants are strongly encouraged to propose using these services as appropriate for their therapeutic development plans with the following restrictions:

• Investigators must conduct at least 40% of the research in the therapeutic development plan at their own institution(s). This means that 40% of the direct costs over the funding period must be used for research at the investigators' institution(s).
• For any research planned to be conducted outside of the investigators' institution(s), including research that may be done through the NHLBI research programs, an estimated cost for the work must be included in the budget.
• For services performed by non-NHLBI research programs, subcontracts may be proposed.
• CADET will not award costs for services provided in-kind through SMARTT, PACT, or GTRP.

Funding Instrument	Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH scientific or program staff will assist, guide, coordinate, or participate in project activities.
Application Types Allowed	New The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.
Funds Available and Anticipated Number of Awards	The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications. NHLBI intends to fund up to 10 awards, corresponding to a total of $75,000,000 for fiscal years 2014-2018.
Award Budget	Direct costs for a single application may be up to $1,000,000 annually.
Award Project Period	For UH2/UH3 applications the maximum project period is five years (two years for the UH2 portion and three years for the UH3 portion). Funded grants will receive UH3 funding contingent on successful completion of pre-negotiated milestones for the UH2 period.

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

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

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

Other

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

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are not allowed.

Applicant Organizations

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

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

Program Directors/Principal Investigators (PD(s)/PI(s))

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

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

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

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

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

NIH will not accept any application that is essentially the same as one already reviewed within the past thirty-seven months (as described in the NIH Grants Policy Statement), except for submission:

• To an RFA of an application that was submitted previously as an investigator-initiated application but not paid;
• Of an investigator-initiated application that was originally submitted to an RFA but not paid; or
• Of an application with a changed grant activity code.

It is anticipated that applicants will benefit from consultation with experts in therapeutic development and may require external collaborators to complete the research needed for their project. Funded projects (and budgets) will be reviewed by the EAB with an assessment of the necessary pre-clinical studies. Final research plans at the time of award must include at least 40% of the research (based on direct cost budget) conducted at the investigators' institution(s).

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

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

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

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

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

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

The letter of intent should be sent to:

Director, Office of Scientific Review
Division of Extramural Research Activities
National Heart, Lung, and Blood Institute, NIH
6701 Rockledge Drive, Room 7214
Bethesda, MD 20892-7924 (Express Mail ZIP: 20817)
Telephone: (301) 435-0270
Fax: (301) 480-0730
Email: nhlbichiefreviewbranch@nhlbi.nih.gov

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

The forms package associated with this FOA includes all applicable components, required and optional. Please note that some components marked optional in the application package are required for submission of applications for this FOA. Follow all instructions in the SF424 (R&R) Application Guide to ensure you complete all appropriate optional components.

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

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

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

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

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

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

The total direct cost for each application cannot exceed $1 million dollars annually, exclusive of the Facilities and Administrative costs of first tier subcontracts. This must include the costs for all research conducted, including work performed at an organization other than the PD/PI institution.

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

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

Research Strategy:

The research strategy should include the following three CADET requirements:

1. Product development plan

a. Must begin with scientific identification of a pathobiologic process and end with IND filing.

b. Must be summarized using a timeline that specifies which of the studies are proposed for support in CADET.

2. Proposed milestones (for both the UH2 and UH3 segments of the grant period).

3. An explicit statement of the IND status of the proposed therapeutic product and how the criteria for a "novel" therapeutic approach as defined in the second CADET requirement for responsiveness have been met.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) as provided in the SF424 (R&R) Application Guide, and should consult with their institution's legal authorities to define how intellectual property resulting from the research will be protected.

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

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

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

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

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

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

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

This initiative is not subject to intergovernmental review.

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

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

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

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

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

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 by the Center for Scientific Review and responsiveness by NHLBI. Applications that are incomplete and/or nonresponsive will not be reviewed.

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

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

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

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

Significance

Does the project address an important problem or a critical barrier to progress in the field? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field? Does this project define a plan to change the treatment or approach to management of a disease based on the application of scientific knowledge?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project? Is there adequate demonstration, particularly in the project timeline, that the Investigator(s) has a sufficient understanding of the therapeutic development process to lead the 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? Does the project include a novel product or novel approach to management based on disease biology?

Approach

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

If the project involves clinical research, are the plans for 1) protection of human subjects from research risks, and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion of children, 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?

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

Relevance of Proposed Research to Regulatory Approval of a Product

Have the investigators demonstrated proficiency in therapeutic development by defining a progression of research that may ultimately lead to IND filing? Are the proposed studies likely to be required for IND application?

Milestones and Timeline

Is there a clear description of the timeline to enable IND filing, the milestones that need to be achieved for the UH2 and UH3 components of the research, and go/no go decision points in the development plan?

Protections for Human Subjects

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

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

Inclusion of Women, Minorities, and Children

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

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

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

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) Genome Wide Association Studies (GWAS).

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.

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by the NHLBI,, in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

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

Appeals of initial peer review will not be accepted for applications submitted in response to this FOA.

Applications will be assigned to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the NHLBI 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.

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

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

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

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

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

Any application awarded in response to this FOA will be subject to the DUNS, SAM Registration, and Transparency Act requirements as noted on the Award Conditions and Information for NIH Grants website.

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

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is applicable when state and local governments are eligible to apply), and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

Definitions

External Advisory Board (EAB): The EAB will be composed of six to ten senior scientists with relevant expertise who are not PDs/PIs of any of the funded applications in CADET who will assist NHLBI staff in the oversight of this program. See more about the EAB below under this topic.

Awardee Rights and Responsibilities

• The awardee will have primary responsibility for all aspects of the proposed research, including any modifications to the product development plan, selection and conduct of the studies to be performed, the plan for who will conduct the necessary research, quality control, data analysis and interpretation, preparation of Regulatory submissions and publications, and compliance with local IRB requirements.
• The awardee must conduct at least 40% of the research in the therapeutic development plan at the grantee institution(s). This generally means that at least 40% of the direct costs over the funding period will be used for research at the investigators' institution(s).
• The awardee agrees to address the recommendations from NHLBI Staff based on assessments of the EAB.
• The awardee agrees to accept close coordination, cooperation, and participation of NIH CADET staff in those aspects of scientific and technical management of the project as described under "NIH Program Staff Responsibilities."
• The awardee will act as needed to protect intellectual property that may result from work conducted with support of this grant. Any inventions which result from CADET funded research will be reported to the Division of Extramural Inventions & Technology Resources, NIH, within 2 months of the inventor's initial report to the grantee/contractor organization.
• The reporting of inventions will be accomplished electronically through the NIH Interagency Edison Invention Reporting System.
• The awardee will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access and requirements for dissemination consistent with current DHHS, PHS, and NIH policies.

NHLBI Staff Responsibilities

• One NIH Program Staff member will be assigned to each grantee, but significant decisions will involve a committee of Program Staff members.
• The primary assigned NHLBI Program Staff member will be responsible for the normal scientific and programmatic stewardship of the award.
• NHLBI Program Staff will participate in the continuous monitoring and coordination of research activities.
• NHLBI Program Staff will serve a liaison function for sharing of information among the awardees with regard to methods, best practices, and regulatory issues germane to the development of therapeutics for lung diseases.
• NHLBI Program Staff will assist the PD(s)/PI(s) in accessing research resources, especially those needed in response to recommendations from the External Advisory Board (see below).
• NHLBI Program Staff will negotiate milestones with the awardee as necessary, serving as a liaison between the awardee and appropriate NIH committees and Institute and Center National Advisory Councils.
• The NHLBI reserves the right to withhold funding for the UH3 project if the milestones for the UH2 project have not been successfully completed..
• The NHLBI will constitute an External Advisory Board (EAB) to ensure routine access to expert advice on issues of drug development for pulmonary and sleep disorders. NHLBI Program Staff will:
  • Establish the charge to the EAB
  • Convey materials submitted to the NHLBI by the grantee and establish provisions for assuring the confidentiality of these materials
  • Facilitate discussions on the progress reports submitted by awardees on an annual basis, the product development plans and milestones submitted by awardees and any changes to these plans or milestones as requested by the awardee on an annual basis.
  • Communicate recommendations and modifications suggested by the EAB to the awardee for development plans and milestones, including whether milestones have been achieved.
  • The EAB recommendations will be based on standard requirements for product development as well as the expected time and resources needed to achieve milestones.

Collaborative Responsibilities

• The awardee and NHLBI staff will work collaboratively to adjust the research plan and schedule in response to emerging data.
• The awardee and NHLBI staff will work cooperatively to coordinate research activities to be performed through NHLBI programs such as SMARTT, GTRP, and PACT.

External Advisory Board Responsibilities

The EAB will assist NHLBI staff in the scientific oversight of the program and may be asked to:

• Discuss the product development plans and milestones submitted by awardees and any changes to these plans or milestones as requested by the awardee on an annual basis.
• Propose recommended modifications to development plans and milestones based on standard requirements for product development and expected time and resources needed to achieve milestones.
• Discuss the progress reports submitted by awardees on an annual basis.
• Indicate their assessment of whether agreed milestones have been successfully met.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee of the awardee, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16. Although a decision to fund or not to fund the UH3 portion of the study will be based in part on scientific issues, Dispute Resolution will not be used to resolve disagreements regarding funding decisions for the UH3 award, since NHLBI retains full authority for this intrinsically governmental function.

When multiple years are involved, awardees will be required to submit the annual Non-Competing Progress Report (PHS 2590 or RPPR) and financial statements as required in the NIH Grants Policy Statement.

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

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

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

eRA Commons Help Desk (Questions regarding eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

Web ticketing system: https://public.era.nih.gov/commonshelp
TTY: 301-451-5939
Email: commons@od.nih.gov

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact Center Telephone: 800-518-4726

Web ticketing system: https://grants-portal.psc.gov/ContactUs.aspx
Email: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone: 301-710-0267
TTY: 301-451-5936
Email: GrantsInfo@nih.gov

Michelle Freemer, M.D.
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0202
Email: michelle.freemer@nih.gov

Director, Office of Scientific Review
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0270
Email: nhlbichiefreviewbranch@nhlbi.nih.gov

Dianna Jessee

National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0154
Email: jesseed@nhlbi.nih.gov

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

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92.