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

Part 1. Overview Information
Part 2. Full Text of the Announcement

Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

Purpose

The purpose of this Funding Opportunity Announcement (FOA) is to support studies to evaluate the effect of sex hormones and sex hormone-based therapies on thrombus formation in pre-menopausal women. The primary objective is to generate research that will elucidate the mechanisms by which female sex hormones and sex hormone-based therapies can increase the risk of venous and arterial thromboembolism in pre-menopausal women. Understanding the basic pathophysiology of how sex hormones may induce or potentiate pre-existing (or baseline) risk of thrombosis will strengthen our understanding of the mechanisms underlying thrombus formation in relevant clinical situations of high levels of sex hormones. Examples of such clinical situations are: pregnancy, peripartum, women using contraceptives or undergoing in vitro fertilization. Such research may help identify women at higher thrombotic risk and thus help guide their clinical care. It could also lead to the identification of potential new therapeutics to prevent thrombus formation.

Background

Epidemiological studies have linked exposure to elevated levels of endogenous or exogenous sex hormones with an increased risk of both arterial and venous thromboembolism (VTE) in women. Despite this association, the basic mechanistic pathways and interactions following exposure to estrogens, progesterone, or related compounds, and leading to elevated thromboembolism risk are unclear.

It is estimated that over 100 million women worldwide are exposed to exogenous sex hormones through oral contraceptives (OCA). OCA users have a 2- to 6-fold increase of thromboembolism compared to non-users, and the relative risk of VTE becomes higher with increasing age. During pregnancy, women have a 5- to 10-fold increased risk of thrombosis. The risk is further elevated in the postpartum period (15- to 35-fold), especially during the first 6 weeks after delivery (60-fold). Furthermore, multiple hormonal formulations are currently on the market and many questions remain regarding the effects/synergy of different doses, types, and routes of administration for estrogens and progestins/progesterone. Importantly, African-American women have an increased risk of adverse pregnancy outcomes and may have increased risk factors for thromboembolism as compared to Caucasian women.

Several potential mechanisms may contribute to the high risk of VTE in certain individuals; these warrant further elucidation. Molecular and cellular processes triggered by estrogen and progesterone/progestin signaling are not completely understood. For example, important biological variables yet to be explored include:

1) estrogen receptors (ERs) α and β density and distribution, as well as their expression on different tissues, evolution with age, and functional polymorphisms

2) genetic polymorphisms of ER that may contribute to the variability in hormone-induced thromboembolism risk as modulated by gender, or by race and ethnicity, based on appropriate genomic markers of ancestral origin

3) progesterone signaling in pertinent target cell population

4) pathways leading to direct activation and/or cell-cell interactions of inflammatory and prothrombotic cells (e.g., platelets, red blood cells, monocytes and endothelial cells) and factors

If the first VTE event is to be predicted and prevented, it is important to uncover why some of these pathways/cells become activated and result in thrombus formation in some individuals but not in others. To answer these and other relevant questions, the development and use of informative female animal models or in vitro systems that are adapted to answer clinically-relevant questions in pre-menopausal women are encouraged. The physiopathology effects of sex hormones affecting women during pregnancy should be evaluated separately from those associated with OCA use since the mechanisms underlying thrombus formation in these two instances may be different.

Program Structure

This FOA is utilizing a biphasic funding mechanism (R61/R33) to support two major consecutive experimental requirements. The first phase (R61) will focus on the development and/or the adaptation of relevant investigative models that harness the informative power of novel scientific and technologic developments (e.g., -Omics, induced pluripotent stem cells (iPSC), microfluidics, single cell analysis, or systems biology) to evaluate the effect of sex hormones on thrombus formation in female physiological systems. The second phase (R33) will seek to identify and characterize potential mechanisms underlying sex hormone-induced thromboembolism using the model(s) developed in the first phase.

The R61 Phase (1 to 2 years) is intended to support innovative applications proposing to develop or optimize a model system to examine female sex hormone-induced thrombosis. The R61 phase will provide time for necessary preliminary work, including necessary modifications of existing approaches, methods, or technology. Successful completion of the R61 Phase will justify progression to the second phase of the project (R33). Funding for the R33 phase will be contingent upon successfully meeting the proposed R61 milestones.

The R33 Phase (up to 3 years) is intended to expand upon the developmental/exploratory work of the R61 phase with the aim of identifying and evaluating the basic cellular, molecular and physiological influence of sex hormones on the baseline state of the endovasculature, as well as pathological processes that determine the prothrombotic state induced by endogenous or exogenous perturbations in the sex hormone environment using the pre-clinical model(s) established in first R61 phase.

Multi-PD/PI applications representing investigators with complementary expertise in areas including but not limited to coagulation science, Omics, organ on a chip technology, inflammation, vascular biology, iPSC, hematopoietic stem cell (HSC) and niche biology, are strongly encouraged. Additionally, applicants should leverage other resources such as biospecimens and genomic sequencing data obtained from relevant clinical studies.

Examples of Research Programs

Research that will be supported by this FOA includes but is not limited to the following:

• Investigation of the effect of sex hormones on cell lines derived from female and male tissues.
• Exploration of the direct effect of sex hormones on platelets and endothelial cells produced in human- Induced pluripotent stem cells (iPSCs).
• Development of sex- specific microfluidic models to perform vascular studies of endothelial cells under flow like conditions.
• Identification of key modifier genes regulated by sex hormones in human blood cells using genomic, transcriptomic and/or metabolomic approaches.
• Determination of genetic variations that may contribute to the variability in hormone-induced thromboembolism risk as modulated by gender, race, and ethnicity
• Confirmation of the role of the identified modifier genes by techniques such as micro RNA, siRNA, CRISPR/Cas9 genome editing and other approaches
• Exploration of the indirect effects of sex hormones in inducing thrombosis through inflammation using in vitro cultured liver cells for the production of inflammation and/or coagulation proteins
• Explore the role of sex hormones on inflammatory cells such as lymphocytes, monocytes, macrophages or dendritic cells from female donors
• Use of in silico models that represent the human vasculature system and that can be interrogated by exposure to hormones
• Development of novel female animal models to study function, distribution and variation of sex hormone receptors with age
• Examination of how routes of delivery/doses/combinations of sex hormone therapies affect thrombotic mechanisms
• Exploration of the role of estrogens/ER on hematopoietic stem cells and their niche in contributing to thrombus formation through subsequent effects on megakaryocytic/platelet lineage and erythropoiesis, endothelium/vasculature and osteolineage cells
• Development of real time imaging techniques to follow thrombin-fibrin-thrombosis formation in arteries and veins
• Development of an algorithm for risk stratification of thrombotic risk through the translational study of novel targets and potential biomarkers in human biospecimens from existing deeply phenotyped cohorts

Research that will be considered not responsive to this FOA includes:

• Epidemiologic studies including studies based on electronic medical health records or administrative data files
• Clinical trials
• Studies evaluating efficacy or effectiveness of anti-coagulation therapy for thromboembolism
• Studies exploring post-menopausal women cohorts or samples; this initiative focuses on pre-menopausal women, rather than on post-menopausal women, to better discriminate hormone-induced mechanisms of thrombus formation from those more likely related to the presence of other comorbid conditions that increase with age.

Investigator Meetings:

Funded investigators will be expected to participate in periodic program teleconferences and webinars during the R61 and R33 phases of the award. Additionally, investigators are expected to attend an annual in-person meeting near Bethesda, Maryland, during the R61 and R33 phases of the award.

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

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made 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:

o   Hispanic-serving Institutions

o   Historically Black Colleges and Universities (HBCUs)

o   Tribally Controlled Colleges and Universities (TCCUs)

o   Alaska Native and Native Hawaiian Serving Institutions

o   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 allowed.

Applicant Organizations

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

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

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

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

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

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

This FOA 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.

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

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

Buttons to access the online ASSIST system or to download application forms are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

It is critical that applicants follow the Research (R) Instructions in the SF424 (R&R) Application Guide, including Supplemental Grant Application Instructions 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
National Heart, Lung, and Blood Institute (NHLBI)
6701 Rockledge Drive, Room 7214
Telephone: 301-435-0270
Email: nhlbichiefreviewbranch@nhlbi.nih.gov

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

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

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

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

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

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

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

The R61 budget should include funds for attending an annual grantees' in-person meeting near Bethesda, Maryland.

The R33 budget should include funds for one or two people attending annual grantees' in-person meetings near Bethesda, Maryland.

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

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

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

Specific Aims: Describe and clearly demarcate the specific aims for both the R61 and the R33 phases.

Research Strategy: Describe the research designs, methodologies and milestones for both the R61 and the R33 phases of the award. The R61 and R33 phases must be clearly demarcated.

Applicants should propose a multi-disciplinary approach to study the physiopathology of thromboembolism induced by sex hormones in premenopausal women. Both in vitro and in vivo models can be developed and/or optimized, and then utilized to explore the molecular and/or cellular mechanisms involved in this process.

R61 Phase

Describe the following:

• Background
• Evidence of feasibility of the proposed approach
• Plans for accomplishing the necessary preliminary work (i.e., substantial modification of approaches, methods, or technology during the R61 phase)
• Research strategy and methods for the R61 phase
• Milestones - Include a clear description of the R61 phase milestones that, if met, will justify proceeding with the proposed mechanistic studies in the R33 phase. Milestones must be specific, quantifiable, feasible, and scientifically justified with regard to the specific aims. See Milestones heading below for further information.
• Timeline for the completion of the R61 phase. The timeline should include a discussion of the suitability of the milestones for assessing success in the R61 phase, and a discussion of the implications of successful completion of these milestones for the proposed R33 phase.

R33 Phase

Do not repeat background information or methodology details in the R33 research strategy section that were provided in the R61 section.

Describe the following:

• Milestones - Include a clear description of projected specific, measureable and achievable progress throughout the project period, which can be used as an indicator of success.
• Details of the experimental design including plans for the development and expansion of the R33 phase beyond the work accomplished in the R61 Phase. See Milestones heading below for further information.
• The significance and innovation of the proposed work/research with discussion of how the work will be hypothesis-generating and help elucidate mechanisms by which female sex hormones and sex hormone-based therapy can increase risk of thromboemobolism in pre-menopausal women.
• Timeline for the completion of the R33 phase

Milestones

Adequate identification and evaluation of the basic underlying molecular, cellular and physiological mechanisms by which sex hormones or sex-hormone therapy induce thrombus formation must be a key criterion of the decision to move from the R61 to the R33 phase. Milestones for both the R61 and R33 portion of the project must be specific, quantifiable, feasible, and scientifically justified; not simply a restatement of the specific aims. Stating well-defined, measurable milestones is critical to the application. These will vary depending on the nature of the proposed research, and should be tailored to the applicant’s specific research goals. The clarity and completeness of the R61/R33 application with regard to specific goals and feasibility of milestones are critical. Specify conditions under which the project would not proceed to the R33.

Preliminary Data

The R61 phase will be considered exploratory, so extensive preliminary data from the applicant’s own laboratory is not required. However, the project must be based on a strong rationale, and the applicant should provide evidence that the proposed approach and methods are feasible.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

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 PHS Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.

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

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

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

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

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

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

This initiative is not subject to intergovernmental review.

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

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

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

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

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

Important reminders:

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

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

See more tips for avoiding common errors.

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

Applicants are required to follow the instructions for post-submission materials, as described in the policy.

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.

For this particular announcement, note the following:

The R61/R33 phased innovation grant supports investigation of novel scientific ideas or new interventions, model systems, tools, or technologies that have the potential for significant impact on biomedical or behavioral and social sciences research. A R61/R33 grant application need not have preliminary data, extensive background material or preliminary information; however, they may be included if available. Appropriate justification for the proposed work can be provided through literature citations, data from other sources, or, when available, from investigator-generated data. Accordingly, reviewers will focus their evaluation on the conceptual framework, the level of innovation, and the potential to significantly advance our knowledge or understanding. Reviewers will assign a single impact score for the entire application, which includes both the R61 and R33 phases.

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

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

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

Specific to this FOA:

How strong is the likelihood that the proposed R61 phase will result in the development or optimization of relevant in vivo or in vitro models that can be used to study the physiopathology effects of female sex hormone-induced thrombosis in pre-menopausal women? What is the likelihood that the research proposed for the R33 phase will advance understanding of the mechanisms by which female sex hormones and sex hormone therapy induce thrombus formation in pre-menopausal women?

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?

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:

How effectively is information from the Omics, iPSC, microfluidics, single cell analysis, or systems biology fields incorparated in models proposed in the R61 phase?

Will the models proposed in the R61 phase allow innovative investigations into the mechanisms underlying thrombotic risks in the setting of endogenous or exogenous female sex hormones in pre-menopausal women?

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

Specific to this FOA:

How strong is the likelihood that a useful model will be established during the R61 phase? Are the milestones for assessing success in the R61 phase reasonable and are the implications of successful completion of these milestones relevant to the R33 phase research plans?

How applicable and/or generalizable and/or clinically relevant is the proposed research approach?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of children, justified in terms of the scientific goals and research strategy proposed?

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

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

Milestones

Are quantitative criteria pre-specified and clearly defined to assess milestone achievement and feasibility relevant to advancing from the R61 to the R33 phase? Are R61 milestones feasible, well developed and appropriate, adequately described, and quantifiable with regard to the specific aims? Are quantitative threshold values specified for the proposed milestones? Specifically, will the milestones help determine if the project overall succeeded in developing or optimizing model(s) that help elucidate mechanisms by which female sex hormones and sex hormone-based therapy can increase risk of thromboemobolism in pre-menopausal women? Is the study timeline feasible? Does the application specify conditions under which they would not proceed to the R33 phase?

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

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

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

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

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

Not Applicable

Not Applicable

Not Applicable

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

Not Applicable

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

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

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

Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research. In particular, reviewers will be asked whether the period of the R61 is appropriate.

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

As part of the scientific peer review, all applications:

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

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

Applications will be assigned 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.

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

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

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

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

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

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

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

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

For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see http://www.hhs.gov/ocr/civilrights/resources/laws/revisedlep.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and http://www.hhs.gov/ocr/civilrights/understanding/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at http://www.hhs.gov/ocr/office/about/rgn-hqaddresses.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

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

Cooperative Agreement Terms and Conditions of Award

Not Applicable

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

A final 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.

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

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

eRA Service Desk (Questions regarding ASSIST, eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, 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)

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

Email: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)

Telephone: 301-710-0267

Nahed El Kassar, MD, PhD
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0056
Email: nahed.elkassar@nih.gov

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

Anthony Agresti i
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0166
Email: agrestia@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 Part 75.