It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide,except where instructed to do otherwise (in this FOA or in a Notice from 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.

Purpose

This Funding Opportunity Announcement (FOA) will support the development of collaborative research projects to establish a set of complementary model systems that reproduce essential disease-defining features of human idiopathic pulmonary fibrosis (IPF). The purpose of this initiative is to unify a series of projects encompassing multiple complementary model systems that each effectively reproduces essential disease features of human IPF. This FOA encourages applications to develop research models that will advance our understanding of the pathogenesis of IPF from its onset through disease progression and serve as a resource for the broader research community including investigators testing novel therapies to treat this disease.

Background and Objectives

The most prevalent and deadly interstitial lung disease is IPF, a chronic and progressive condition that currently affects an estimated 132,000 to 200,000 people and causes approximately 50,000 new cases and 40,000 deaths each year in the U.S. alone. Despite considerable research effort and investment, median survival following a diagnosis of IPF remains 3 to 5 years. The lack of preclinical model systems that effectively reproduce the pathologic features of human IPF and can also be exploited to assess drug efficacy is a significant impediment to the realization of clinical treatments stemming from basic IPF research. The most frequently used model to study IPF involves intratracheal delivery of the DNA-damaging agent bleomycin to mice. This model is characterized by widespread acute inflammation and rapidly forming fibrosis that spontaneously resolves. In stark contrast, human IPF is marked by the absence of overt inflammation and defined by non-resolving, progressive pathology classified as usual interstitial pneumonia (UIP). Other less commonly used animal models of IPF similarly reproduce some but not all disease features and the effects are often strain-specific. Moreover, the relevance of findings in these animal models is difficult to assess in the absence of a complementary in vitro model that utilizes human tissue. As such, there is a critical and unmet need for improved research tools and resources that facilitate the study of IPF and further the development and testing of novel therapeutics to treat this devastating disease.

The weight of current evidence suggests that the pathogenesis of IPF involves the aberrant intersection of diverse cellular and molecular pathways. Repetitive injury to the alveolar epithelium is thought to initiate the processes that have been observed in the lungs of patients with mild to moderate IPF: increased apoptosis/senescence of the alveolar epithelium, localized proliferation of repair-associated myofibroblasts, and excess extracellular matrix including collagen deposition. Slowly over time and in association with the aging process, an accumulation of these events is believed to produce the histopathological features of advanced IPF, such as patchy subpleural and basilar-predominant interstitial thickening, fibroblastic foci, and cystic dilation of the alveoli and bronchioles that eventually lead to a progressive decline in lung function and clinically apparent symptoms. Studying the insidious onset of these wide-ranging pathological features is further complicated by spatial and temporal heterogeneity among fibrotic zones, with areas of normal lung architecture interspersed with regions of dense fibroblastic foci even within the same lobe of a lung. Given that no single-model system is likely to fully recapitulate these disparate aspects of IPF, the purpose of this FOA is to unify a series of projects encompassing multiple complementary model systems that each effectively reproduces essential disease features of human IPF. The objective of this program is to yield models that may range from animal to human and cellular to whole-organism, display non-resolving or progressive aspects of lung fibrosis, and contain at least one of a specified set of disease-defining elements.

Disease-defining Elements:

• Elevated gene expression or protein production of human IPF-associated markers
• Aberrant hematopoietic, mesenchymal, or epithelial cell function that signifies excessive apoptosis, senescence, or activation of lung tissue repair-associated pathways
• Heterogeneous fibrotic histopathology of the lung interstitium or imaging characteristics consistent with usual interstitial pneumonia (e.g. patchy subpleural and basilar-predominant interstitial thickening, fibroblastic foci, cystic dilation of the alveoli and bronchioles, heterogenous paraseptal fibrosis with architectural distortion, predominately peripheral bilateral reticulation and honeycombing, traction bronchiectasis)
• A decline in pulmonary function indicative of fibrotic change to include restrictive physiology and impaired gas exchange
• Fibrotic lung disease that occurs naturally or in association with aging of a lung cell or tissue

The release of this FOA is consistent with the recommendations put forth by a NHLBI workshop “Future Directions in Idiopathic Pulmonary Fibrosis Research” (Blackwell et al. 2014 Jan 15;189(2):214-22), which included a directive to advance novel research models to study pulmonary fibrosis. It is anticipated that the integrated, multi-project approach to this FOA will serve to coalesce a suite of individual models that together serve to form one larger, improved model system for IPF that will offer greater potential for the translation of basic IPF discoveries into clinical care.

Consortium Activities

This initiative intends to fund up to five U01 cooperative agreements working together as a consortium. Among awarded cooperative agreements, one will be selected to also perform the activities of the Administrative Coordinating Center (ACC). The ACC will serve all grantees awarded U01 cooperative agreements with a range of administrative functions, including organizing Steering Committee meetings, arranging conference calls, establishing an external advisory board, and taking stewardship for maintaining and publishing protocols related to model development and usage. Details of how to apply for the ACC are in Section IV. "Application and Submission Information".

Awardees will meet in person within three months after the project's start date for a Planning Meeting and once per year thereafter in Bethesda, Maryland for Steering Committee meetings. These meetings will be used to coordinate activities across the consortium and maximize the research productivity of the program as a whole. The meetings will allow sites to leverage each other's strengths and maximize the opportunities for discovery.

Research Scope

Projects that include the development of a cellular, organ(oid), or whole-organism model derived from either human or animal tissues, and that seek to better understand, detect, or resolve IPF, are all responsive to this FOA. Establishing models that range from in vitro human cell culture through 3D lung organoids and small and large animals is intended to enable investigators to conduct hypothesis testing across both the spectrum of disease progression and all phases of preclinical drug development.

The following are examples of research topics responsive to this FOA. These are only examples; applicants should not feel limited to the subjects mentioned and are encouraged to submit other topics pertinent to the objectives of this FOA.

• Validation of a cellular or organoid model derived from human IPF tissues for testing anti-fibrotic drugs
• Establishment of a humanized animal model that permits the study of human cells derived from human IPF tissue or human cells derived from normal tissue and exposed to fibrotic stimuli in vivo
• Further studying the existence of naturally occurring fibrosis in an animal model
• Application of lung-on-a-chip technology to establish an in vitro model of pulmonary fibrosis
• Modification and refinement of existing pulmonary fibrosis models, with the exception of bleomycin-induced fibrosis, such that they induce chronic and progressive fibrotic pathology consistent with usual interstitial pneumonia
• Establishment of a model that can be used to evaluate differences in young versus aged/senescent cells or animals in response to fibrotic stimuli or anti-fibrotic therapies
• Development of a model system that permits investigation of factors that contribute to differential fibrotic responses in males and females
• Inducing early-onset fibrosis in a cell line, organoid, or animal model through manipulation of the genome or introduction of epigenetic changes

The following types of projects will be considered non-responsive to this FOA and will be returned without review:

• Applications without evidence that the proposed model induces non-resolving or progressive aspects of lung fibrosis, or that lack inclusion of one or more of the five disease-defining elements listed above.
• Applications that propose to utilize an existing model of bleomycin-induced fibrosis.
• Applications that propose clinical trials.

Additional Considerations

Applicants with experience in preclinical model development and expertise in clinical pulmonary fibrosis are highly encouraged. It is preferred that projects have a clinician as a formal member of the investigative team. Alternatively, a letter of support from a collaborating clinician can be used to demonstrate involvement in the project, but should include a plan for collaboration with the principal investigator. The clinician should have demonstrated experience in the study of clinical IPF.

Applicants are strongly encouraged to contact Scientific/Research staff to discuss potential research projects prior to submitting an application.

Small Business applicants who are eligible for the Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) programs are strongly encouraged to submit through either the SBIR or STTR Omnibus Solicitations (https://sbir.nih.gov/funding#omni-sbir) to take advantage of the congressionally mandated set-aside specifically for small businesses.
See Section VIII. Other Information for award authorities and regulations.

1. Eligible Applicants

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)

• Eligible Agencies of the Federal Government

• U.S. Territory or Possession

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

Applicant organizations

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

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

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

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

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.

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications  

The NIH will not accept duplicate or highly overlapping applications under review at the same time.  This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101)

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
National Institutes of Health
Bethesda, MD 20892
Telephone: 301-435-0270
Email: NHLBIChiefReviewBranch@nhlbi.nih.gov

Other Attachments:

Administrative Coordinating Center

There will be one Administrative Coordinating Center (ACC) to service all projects across the program. Applicants that wish to be considered for the ACC must submit a description of how they will carry out the functions of the ACC. The file name "Admin Coordinating Ctr.pdf" should be used and may not exceed 3 pages. Only one ACC site will be selected from the applicants who wish to be considered and will receive additional funds to support the ACC activities.

To be considered for the ACC, describe plans to accomplish/carry out the required functions of the ACC. Include a description of:

• How Planning and Steering Committee meetings will be arranged, managed, and organized
• Plans for arranging investigator conference calls
• Plans for designing and maintaining a website to support the consortium  
• Plans for establishing an external advisory board to provide guidance to awardees on appropriate milestones and criteria for model success and key model features that would directly facilitate pre-clinical drug discovery and efficacy testing
• Plans for ongoing internal management related to the development of protocols to integrate and optimize use of the proposed models
• Plans for coordinating the publication of methods paper(s) to increase visibility and usability of the models for the broader research community
• Plan for facilitating the dissemination of best practices for model development based on lessons learned within the program and the transfer of model-associated resources into publicly available repositories  

PD(s)/PI(s) should describe any prior experience working productively in collaborative programs. Applicants that wish to be considered for the ACC must include an ACC director with the qualifications necessary to manage the facility.

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

Administrative Coordinating Center (ACC):

An additional $80,000 in direct costs in the first year and $100,000 in direct costs in years 2-4 will be budgeted for one site selected to serve as the ACC for the entire program. The proposed ACC budget should include costs associated with:

• Arranging the Planning Meeting and subsequent annual Steering Committee meetings, as well as meetings of the External Advisory Committee
• Conducting four to six conference calls per year
• The design and maintenance of a consortium website
• Travel costs for the consortium PIs to attend the required in-person meetings in Bethesda, MD
• Publication costs of methods paper(s)
• A minimum of 0.6 person months will be required for the ACC director

Specific Aims: Briefly provide the context and overall rationale for the proposed set of studies, with an emphasis on the rationale that the proposed model system will serve as a resource for the broader research community including investigators testing novel therapies to treat human IPF. In addition, the major objectives of the proposed set of studies should be stated, including the technical questions to be answered to determine the feasibility of the proposed model systems and validation testing schemes to demonstrate relevance of the model system to the clinical setting.

Research Strategy: The Research Strategy section should include the following sections:

Rationale and Unmet Need

• Rationale for the proposed model system which includes any existing clinical evidence that the model system and validation approaches are relevant in human IPF (how well the model system will recapitulate the deficits, pathology, disease progression, and genetic basis of the human disease compared to current models).
• Biological rationale for the proposed model system as it relates to the current knowledge of disease etiology or targeted pathways for potential therapeutics.
• Description of the novelty of the model system along with the potential advantages of the proposed model over currently available alternatives.
• Description of the unmet need for the proposed model system.
• Description of how the proposed model system is amenable to integration with other IPF models in a complementary fashion.

Value for Understanding IPF Disease Pathogenesis and Future Drug Discovery/Development

• Brief discussion of the value of the proposed model system in improving our knowledge base and hypothesis-testing in the context of IPF disease persistence and progression. Address how the model system could be utilized in the drug discovery/development process (i.e., proof of concept studies, preliminary efficacy or toxicology testing, evaluating pharmacokinetic or pharmacodynamic parameters for biomarker discovery, as a tool for evaluating target engagement etc.).

Approach

• Description of how the model system will be produced, including a plan to confirm the feasibility and applicability of the model system and proposed testing modalities.
  1) Is there evidence that the endpoints for evaluating the model system are relevant to the clinical setting?
  2) If the model requires breeding or aging, will sufficient animals be available to conduct validation studies within the 4-year limit of the funding period?
  3) What are the plans to optimize (if necessary) the model system in order to conduct the studies required to provide external validation of the model system?

The Research Strategy should also clearly describe the management plan for the proposed collaborative research. In particular, outline plans and mechanisms to keep the project focused and progressing:

• Set realistic and quantifiable intermediate milestones on a timeline to allow for the evaluation of progress towards the project's goal. Progress towards these milestones will be assessed by NHLBI project staff on a regular basis; consistent failure to achieve milestones may result in termination of the award.
• Explain how collaborators can be added or removed as the expertise, knowledge, and skills necessary to advance the project evolve.
• Describe how intellectual property issues will be handled.

Collaboration: NHLBI strongly encourages applicants to form multidisciplinary teams that consist of academic/industry experts relevant to the research plan (i.e., basic science researchers, biostatisticians, clinicians, technical and regulatory experts). This multidisciplinary team should be able to define the goals of the research, outline specific gaps that need to be addressed during this funding period, outline detailed plans and experiments, and execute the research strategy.

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.
• Applicants should address the following:
  • Availability of biological resources utilized and/or developed (mouse models, cell lines, reporter systems, vectors, molecules, antibodies, biomarkers, etc.)

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

Study Record: PHS Human Subjects and Clinical Trials Information

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

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

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

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

4. Submission Dates and Times

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

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

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

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

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

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

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

7. Other Submission Requirements and Information

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

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

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

Important reminders:

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

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

See more tips for avoiding common errors.

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

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.

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? 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:

To what extent does the proposed model system have relevance to clinical IPF in terms non resolving and/or progressive aspects of lung fibrosis, to include: elevated gene expression or protein production of human IPF-associated markers; aberrant hematopoietic, mesenchymal, or epithelial cell function that signifies excessive apoptosis, senescence, or activation of lung tissue repair-associated pathways; heterogeneous fibrotic histopathology of the lung interstitium or imaging characteristics consistent with usual interstitial pneumonia (e.g., patchy subpleural and basilar-predominant interstitial thickening, fibroblastic foci, cystic dilation of the alveoli and bronchioles, heterogenous paraseptal fibrosis with architectural distortion, predominately peripheral bilateral reticulation and honeycombing, traction bronchiectasis); a decline in pulmonary function indicative of fibrotic change to include restrictive physiology and impaired gas exchange, and/or fibrotic disease that occurs naturally or in association with aging of a lung cell or tissue?   How likely is the model system to significantly advance our understanding of human IPF pathogenesis? How amenable is the model system to utilization for developing or testing novel IPF therapeutics?

Investigator(s)  

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

Specific to this FOA:

How strong is the provided evidence that the proposed investigator team has the required experience to conduct complex, multi-component, and collaborative research programs? To what extent does the investigative team (including the PD(s)/PI(s)) demonstrate the necessary scientific, clinical, and operational expertise to develop human-relevant model systems? How strong is the track record of success of the investigators in the IPF field? How successful have the investigators been at translating technologies from the discovery phase into validated tools for use by the broader research community? How likely is the proposed management structure to facilitate synergistic collaborative research among the investigative team and to keep the project focused and progressing towards achieving project milestones?

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 does the proposed model system deviate from existing models of IPF and thus represent an innovative surrogate for studying human IPF? To what degree do the properties of the proposed model system provide advantages over existing models of IPF?

Approach  

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

Specific to this FOA:

How well-justified is the scientific rationale for developing the proposed model system based on the available data? How feasible are the proposed strategy, timeline, and benchmarks for success during model system development? To what extent are the approaches to develop the model system scientifically sound? How appropriate, rigorous, and relevant to human IPF are the proposed approaches to validate the model system? To what degree is the model system amenable to integration with other IPF models in a complementary fashion?

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?

Protections for Human Subjects  

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

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

Inclusion of Women, Minorities, and Individuals Across the Lifespan  

When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of individuals of all ages (including children and older adults) to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

Vertebrate Animals  

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

Biohazards  

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

Resubmissions  

Not Applicable

Renewals  

Not Applicable

Revisions  

Not Applicable

Review Considerations for the Administrative Coordinating Center (ACC)

The ACC will receive a review based on the considerations below.

• Are the expertise, training, and experience of the investigators and staff, including the administrative abilities of the proposed ACC Director, appropriate to lead the ACC?
• Is the amount of time proposed to devote to the ACC sufficient to provide for adequate coordination and collaboration?
• Do the proposed administrative, supervisory, and collaborative arrangements provide for achieving the goals of the program, including a willingness to cooperate with the participating projects and the NHLBI?
• Are the quality of the facilities, equipment, and organizational structure appropriate to coordinate the program's activities?

The proposed ACC will be rated as "Recommended" or "Not Recommended" by the review panel based on whether it has the capability to fulfill the required functions of the coordinating center as outlined in Section IV: Application and Submission Information and the overall goals of the program as outlined in Section I: Funding Opportunity Description, and will comment on the strengths and weaknesses of the proposed approaches, resources, and interactions; whether the investigators are qualified for their role(s) in the ACC and have dedicated appropriate time and effort commensurate with the complexity of its functions; and whether the proposed budget for the ACC is appropriate.

Applications from Foreign Organizations  

Not Applicable

Select Agent Research  

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

Resource Sharing Plans  

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

Authentication of Key Biological and/or Chemical Resources:  

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

Budget and Period of Support  

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

2. Review and Selection Process

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

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

• Will receive a written critique.

Applications will be assigned 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 National Heart, Lung, and Blood Advisory Council. The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.
• The potential for synergy will be considered in the selection of the complement of projects.

3. Anticipated Announcement and Award Dates

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

1. Award Notices

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

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

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

2. Administrative and National Policy Requirements

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

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

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

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR 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.

The PD(s)/PI(s) will have the primary responsibility for:

• Awardees will have primary and lead responsibilities for the project as a whole, including research design, protocol development, and collaborations with other awardees, as well as participant recruitment and follow-up, data collection, quality control, interim data and safety monitoring, if applicable.
• All aspects of the scientific activities, including defining the approaches, planning, conduct, analysis, and publication of results, interpretations, and conclusions of studies conducted under the terms and conditions of the cooperative agreement award.
• Serving on the Steering Committee and attending the Planning Meeting and one Steering Committee meeting in the first year, as well as one Steering Committee meeting a year in subsequent years and applicable teleconference calls with NHLBI and Administrative Coordinating Center staff.
• Accepting and implementing the goals, priorities, procedures, protocols, and policies agreed upon by the Steering Committee, and being responsible for close coordination and cooperation with the components of the consortium including the Administrative Coordinating Center and NHLBI staff.
• Upon completion of the project, awardees are expected to put their data into the public domain and/or make them available to other investigators, according to the approved plan for making data and materials available to the scientific community and the NHLBI for the conduct of research at no charge other than the costs of reproduction and distribution.
• Developing and maintaining a communication plan with the Administrative Coordinating Center throughout the duration of the study.
• Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.

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

• The NHLBI Project Scientist will participate in investigator meetings and serve on the Steering Committee; (s)he or another NHLBI scientist may serve on other study committees when appropriate.
• The NHLBI Project Scientist (and the other cited NHLBI scientists) may work with awardees on study issues and, as appropriate, other committees, e.g.: development of common measures and methods, development and conduct of consortium-wide research as appropriate, human subject issues, data sharing issues, quality control, adherence to protocol, assessment of problems affecting the study and potential changes in the protocol, interim data and safety monitoring, final data analysis and interpretation, and preparation of publications.
• The NHLBI reserves the right to phase out or curtail the study (or an individual award) in the event of (a) failure to participate in consortium activities and collaborative research, (b) substantial shortfall in subject recruitment, (c) substantive changes in the agreed-upon methodologies and tools with which NIH cannot concur, (d) human subject ethical issues that may dictate a premature termination, or (e) results that substantially diminish the scientific value of study continuation.
• Additionally, an agency program official or NHLBI program director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.

Areas of Joint Responsibility include:

The investigators will meet at least quarterly via teleconference or videoconference to discuss opportunities for implementing common experimental protocols and for data and resource sharing, and to discuss study progress and challenges, preliminary results and analyses in progress. The PIs and NIH staff will also meet in person in Bethesda, Maryland during the first 3 months of the program for a Planning meeting and once per year for Steering Committee meetings thereafter.

Steering Committee (SC) - The NHLBI Project Scientist and PIs from the projects funded through this FOA will be responsible for forming a Steering Committee as described below. The SC will be the main governing board of the consortium. It will develop collaborative protocols, identify technological impediments to success and strategies to overcome them, and identify opportunities for sharing techniques and tools that might be developed.

• The SC will be composed of the PDs/PIs from the awarded sites and the NHLBI Project Scientist. A single PD/PI from each award site will have one vote. The NHLBI Project Scientist will have one vote. The SC chairperson will be appointed by the NHLBI.
• The SC may, as it deems necessary, invite additional, non-voting scientific advisors to meetings at which research priorities and opportunities are discussed. The NIH reserves the right to augment the scientific expertise of the Steering Committee when necessary.
• There will be one Steering Committee meeting annually, in the Bethesda, MD area.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. The three members will be: a designee of a committee composed of the consortium PIs, chosen without NIH staff voting; one NIH designee; and a third designee with expertise in the relevant area who is chosen by the other two. In the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

3. Reporting

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

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

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

eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten submission by the due date, and post-submission issues)

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

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: GrantsInfo@nih.gov (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: support@grants.gov

Matt Craig, PhD
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0222
Email: matt.craig@nih.gov

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

Nina Hall
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0166
Email: nina.hall@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.