Part I Overview Information

Department of Health and Human Services

Participating Organizations
National Institutes of Health (NIH), (http://www.nih.gov/)

Components of Participating Organizations
National Heart, Lung, and Blood Institute (NHLBI), (http://www.nhlbi.nih.gov/)
National Institute on Aging (NIA), (http://www.nia.nih.gov/)
National Institute of Nursing Research (NINR), (http://www.ninr.nih.gov/)
Office of Dietary Supplements (ODS), (http://dietary-supplements.info.nih.gov/)

Title: Nutrition and Diet in the Causation, Prevention, and Management of Heart Failure

Announcement Type
New

Update: The following update relating to this announcement has been issued:

Program Announcement (PA) Number: PA-05-089

Catalog of Federal Domestic Assistance Number(s)
93.837, 93.866, 93.361

Key Dates
Release Date: April 15, 2005
Letters of Intent Receipt Date(s): Not Applicable
Application Submission Dates(s): Standard dates apply, please see http://grants.nih.gov/grants/funding/submissionschedule.htm for details
Peer Review Date(s): See http://grants.nih.gov/grants/funding/submissionschedule.htm#reviewandaward for guidance on dates.
Council Review Date(s): See http://grants.nih.gov/grants/funding/submissionschedule.htm#reviewandaward for guidance on dates.
Earliest Anticipated Start Date: See http://grants.nih.gov/grants/funding/submissionschedule.htm#reviewandaward for guidance on dates.
Additional Information To Be Available Date (Url Activation Date): Not Applicable
Expiration Date for R21 Application: March 2, 2006
Expiration Date for R01 Non-AIDS Applications: November 2, 2006
Expiration Date for R01 AIDS and AIDS-Related Applications: January 3, 2007

Due Dates for E.O. 12372
Not Applicable

Additional Overview Content

Executive Summary

The purpose of this Program Announcement is to encourage submission of investigator-initiated research applications on the role of nutrition and diet in the causation, prevention, and treatment of cardiomyopathies and heart failure. Basic, translational, and applied interdisciplinary research applications with rigorous hypothesis-testing designs for projects in animals or humans are of interest. The overall goal is to develop a satisfactory science base for preventive approaches in high-risk individuals and for rational nutritional management of patients in various stages of heart failure.

This funding opportunity will use the R01 and R21 award mechanisms. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. The total amount awarded and the number of awards will depend upon the mechanism, numbers, quality, duration, and costs of the applications received.

Applications may be submitted by any individual with the skills, knowledge, and resources necessary to carry out the proposed research. Eligible domestic and foreign institutions/organizations include for-profit or non-profit, public or private, and faith-based or community-based organizations, units of state and local governments, and eligible agencies of the federal government.

Applicants may submit more than one application, provided they are scientifically distinct.

See Section IV.1 for application materials.

Telecommunications for the hearing impaired is available at: TTY 301-451-5936.

Table of Contents

Part I Overview Information

Part II Full Text of Announcement

 Section I. Funding Opportunity Description
    1. Research Objectives

 Section II. Award Information
   1. Mechanism(s) of Support
   2. Funds Available

 Section III. Eligibility Information
   1. Eligible Applicants
    A. Eligible Institutions
    B. Eligible Individuals
   2.Cost Sharing or Matching
   3. Other - Special Eligibility Criteria

 Section IV. Application and Submission Information
   1. Address to Request Application Information
   2. Content and Form of Application Submission
   3. Submission Dates and Times
    A. Submission, Review and Anticipated Start Dates
     1. Letter of Intent
    B. Sending an Application to the NIH
    C. Application Processing
   4. Intergovernmental Review
   5. Funding Restrictions
   6. Other Submission Requirements

 Section V. Application Review Information
   1. Criteria
   2. Review and Selection Process
    A. Additional Review Criteria
    B. Additional Review Considerations
    C. Sharing Research Data
    D. Sharing Research Resources
   3. Anticipated Announcement and Award Dates

 Section VI. Award Administration Information
   1. Award Notices
   2. Administrative and National Policy Requirements
   3. Reporting

 Section VII. Agency Contact(s)
   1. Scientific/Research Contact(s)
   2. Peer Review Contact(s)
   3. Financial/ Grants Management Contact(s)

 Section VIII. Other Information - Required Federal Citations

Part II - Full Text of Announcement
Section I. Funding Opportunity Description

1. Research Objectives

The purpose of this Program Announcement is to encourage submission of investigator-initiated research applications on the role of nutrition and diet in the causation, prevention, and treatment of cardiomyopathies and heart failure. Basic, translational, and applied interdisciplinary research applications with rigorous hypothesis-testing study designs using animals or humans are of interest. The overall goal is to develop a satisfactory science base for preventive approaches in high-risk individuals and for rational nutritional management of patients in various stages of heart failure.

Background

Public Health Need

Heart failure (HF) syndromes are frequently fatal illnesses in which the heart loses its ability to pump effectively in response to the body's needs. HF is typically a chronic disease, with progressive deterioration of ventricular function occurring over a period of years or even decades. Patients may become incapable of performing even the simplest activities of daily living and are at very high risk of medical complications and death.

Congestive heart failure (CHF), the most severe clinical manifestation of HF, poses an enormous national public health burden. 4.9 million Americans live with CHF. 550,000 new cases are diagnosed yearly, and the average duration of disease is ~9 years. In 2002 CHF accounted for 56,000 deaths, $15 billion in hospital costs, and $28 billion in total costs attributable to health care expenditures and lost productivity. Elderly individuals are at particularly high risk of developing CHF; indeed, CHF is the leading hospital discharge diagnosis from medical wards among this age group. Systolic HF is the most common form found in the elderly. Diastolic HF also occurs frequently in the aged, presenting with dyspnea and decreased exercise tolerance Elderly women are the individuals who are most at risk of developing diastolic HF.

The influence of nutrition on HF phenotypes is poorly understood, although epidemiologic and mechanistic evidence is emerging that dietary factors and alterations in myocardial nutrient metabolism may play a critical role in the development and progression of the disease. This implies that dietary modifications might reduce risk of developing HF or might delay progression to more severe forms. In addition, patients with advanced cardiomyopathies or CHF, including those treated by mechanical assist devices or cardiac transplantation, typically suffer from severe nutritional debilitation. Little guidance is available at present regarding optimal nutritional approaches for advanced cases, but dietary management represents a potentially cost-effective means of improving clinical outcomes for these patients.

Nutrition as a causal factor for heart failure

Nutritional factors have long been etiologically implicated in the development of cardiomyopathies, particularly in animals; the veterinary and agricultural literature provides a thorough documentation of multiple types of nutritional cardiomyopathies in species as diverse as swine, cats, dogs, foxes, rodents, and herbivores. These primarily reflect dietary deficiencies or excesses of micronutrients such as vitamins or trace elements, sometimes in the context of dietary stress from protein restriction or high polyunsaturated fatty acid intake.

Relatively little is known about the external factors that influence the development and severity of HF in humans. In unusual situations, nutritional deficiencies may contribute to the development of human cardiomyopathy; one example is that seen in the interaction of coxsackie virus and selenium/vitamin E deficiency in fostering the development of Keshan disease. Some cases of HF are attributable to agents that directly promote myocardial toxicity, such as excessive intake of alcohol, use of cocaine, or treatment with certain cancer chemotherapeutic agents. Most cases of HF, however, are linked to well-known risk factors for coronary artery disease. The most striking of these is pre-existing hypertension, which appears to be both indirectly and directly linked to HF, as it is a risk factor for coronary artery disease and also is considered to result directly in the development of diastolic HF. For relatively weak contributors such as diet or nutrition, the best way to obtain unbiased estimates of long-term risk is through the use of prospective cohort studies that enroll groups of healthy individuals and then track the development of disease over time. In fact, recent evidence from large, long-term follow-up studies has suggested that dietary and nutritional factors can act as effect modifiers for risk factors such as hypertension, but also may have independent and possible causal effects on HF risk. The role of alcohol is not well understood, with relatively modest intakes appearing protective, but the mechanisms for such an effect are not defined. The strongest evidence to date implicates elevated body mass index, high sodium intake, and elevated homocysteine levels as causal or facilitative in raising risk of HF.

Mechanistic research reinforces the likelihood that the observed epidemiologic findings reflect causal relationships rather than chance associations or confounding. For example, deleterious effects on myocardial function and metabolism, and even myocardial structure, have been observed under controlled conditions for animals and/or humans with varying degrees of obesity, insulin resistance, diabetes, and energy deficiency states such as starvation and anorexia nervosa. Conversely, poor myocardial function can lead to distortions of energy balance as seen in cardiac cachexia or growth failure in children with congenital heart defects. Dietary lipid alterations may have direct myocardial effects, as seen in cholesterol cardiomyopathy of rabbits and long-chain fatty acid accumulation in humans. Also, certain micronutrient imbalances, particularly of electrolyte minerals and trace elements, have been found to adversely affect myocardial function. For most vitamins, however, the role in cardiac function is not well defined, with the exception of thiamine. Non-nutritive dietary compounds (such as coenzyme Q, taurine, and carnitine) that are found in food but also are ingested as dietary supplements have been studied with mixed results; the effects of these compounds on myocardial function are poorly understood.

Nutrition in the management of heart failure

Compared with nutrition guidelines for other cardiovascular conditions, those for HF are minimal. Patients and care providers alike seek well-integrated, robust nutritional guidance that accounts for specific therapeutic needs at various stages of disease, but also places them in a complete dietary context. Thus more information is needed in various HF patient populations regarding dietary macronutrient composition, overall dietary patterns (such as the DASH diet), and the appropriate usage of dietary supplements. Information particularly is needed regarding appropriate weight loss modalities for HF patients who are obese or overweight. Also, given recent recommendations that most HF patients should engage in therapeutic exercise regimens, a better understanding is needed of the role of nutrition in improving exercise tolerance. For example, glycogen-sparing diets may be able to enhance exercise capacity in HF, but have not been tested widely in different patient subgroups, such as those with concurrent diabetes.

Advanced-stage HF patients treated with surgical approaches have unique nutritional problems that to date have been only minimally addressed. Nutritional concerns among patients receiving left ventricular assist devices include impaired gastrointestinal function and high risk of nutrient depletion. Similarly, the optimal nutritional management of cardiac transplant patients is not well developed; problems include pre-transplant debilitation and post-transplant drug-nutrient interactions, obesity, hyperhomocysteinemia, and hyperlipidemia. Better approaches are needed for characterizing nutritional status and managing nutritional support in such patients.

Although dietary guidance often is a component of multi-disciplinary team management of HF patients, it usually is difficult to identify the specific benefits and cost effectiveness of nutrition services compared with other treatment modalities. This is particularly important for HF patients, given that many hospitalizations are ascribed to deviations from diet and medication. Outpatients and hospitalized patients with HF need to be studied in terms of how to achieve good adherence and how to separate adherence vs. efficacy effects for dietary modifications. Research also is needed on behavioral, psychosocial, family support, and other factors that affect the ability of HF patients to achieve adherence to dietary recommendations.

Summary of research needs

Hypothesis-testing research is needed to identify plausible biological mechanisms and to clarify the roles of specific foods, nutrients, and dietary patterns in the development and progression of HF. Information is needed regarding applicability of veterinary, farm, and other animal models of nutrition-related HF to the human situation. Data are particularly needed in relation to the basic etiology and pathophysiology of cardiomyopathies and HF.

There is a dearth of both observational and mechanistic studies related to nutrition in adult and pediatric HF patients at all stages of the disease. Regardless of the original cause of the disease, patients with advanced cardiomyopathies or HF typically suffer from severe nutritional debilitation, but little guidance is available regarding optimal dietary management of such patients. Furthermore, rational dietary management of patients with relatively mild HF has not been fully explored, especially as an adjunct to pharmacologic therapy. Appropriate investigations into delivery of nutrition-related health services also are needed. These would have real potential to generate data that can help in decisions related to design of health care systems, effectiveness of behavioral interventions, and cost effectiveness of various treatment paradigms.

Other topics of interest include studies of cardiac lipotoxicity (especially in association with obesity), “cardiac cachexia” and other problems of energy balance and metabolism, and nutrient metabolism in HF. There is a need for a more precise definition of cardiac cachexia (based on objective endpoints), as well as research to evaluate its effects on whole body metabolism and cardiac function, and on its treatment. The role of dietary supplements in the management of HF patients needs to be better defined. Evaluations also are needed regarding the potential utility of dietary regimens and nutritional modifications for improving clinical outcomes in patients with HF, cardiomyopathy, heart transplants, or implantable devices.

A diverse array of investigator-initiated projects, solicited through this PA, could effectively broaden the knowledge base on nutrition and HF. Most trials to date have been short-term and underpowered; the results have been hard to interpret, especially in the context of concurrent pharmacologic therapy; and the cardiac and nutritional endpoints often have been inadequate, preventing robust conclusions. The greatest impact is expected to derive from small, focused, mechanistic studies that can provide a high-caliber evidence base for rational nutritional management of patients in various stages of HF. Such studies should be designed by multidisciplinary teams of investigators including cardiologists, nurses, and nutritionists.

Appropriate designs for studies in humans would address: statistical power; effect size of the intervention; appropriate homogeneity or heterogeneity of patient populations for testing the hypotheses of interest; potential confounding factors; time course of treatment; drop-out rates; dietary intake and nutritional status assessment; treatment compliance methodology; and intermediate measurements and surrogate endpoints relevant to HF research, including biological, clinical, and behavioral responses to specific interventions.

Epidemiology studies focused on the interaction between nutritional status and cardiac function/HF also are needed. Population studies also could be useful in assessing diet-disease risk relationships in population subsets such as patients with obesity, diabetes mellitus, and the metabolic syndrome. Use of established cohorts or existing data sets could provide an efficient research approach, i.e., taking advantage of longitudinal or cross-sectional studies in which nutritional status, dietary, and cardiac function/structure endpoints were measured Existing data sets also could be a valuable resource for hypothesis-generating analyses and could provide descriptive data that might be the basis for power calculations for more focused studies.

Suitable topics for research include, but are not limited to, the following:

See Section VIII, Other Information - Required Federal Citations, for policies related to this announcement.

Section II. Award Information

1. Mechanism(s) of Support

This funding opportunity will use the NIH Research Project Grant (R01) and Exploratory/Developmental Grant (R21) award mechanisms.

As an applicant, you will be solely responsible for planning, directing, and executing the proposed project.

This funding opportunity uses just-in-time concepts. It also uses the modular as well as the non-modular budget formats (see http://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, if you are submitting an application with direct costs in each year of $250,000 or less, use the modular budget format described in the PHS 398 application instructions. Otherwise follow the instructions for non-modular research grant applications.

2. Funds Available

Applications received in response to this program announcement will compete for funds in the general funding pool of the participating NIH ICs. No specific funds have been set aside for this announcement. The number and size of the awards will depend on the number of applications received, their relative scientific merit, and the general availability of funds for investigator-initiated research at the participating ICs.

Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the NHLBI, NIA, NINR, and ODS provide support for this program, awards pursuant to this funding opportunity are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications.

For the R01 award mechanism, the applicant may request a project period of up to 5 years For applications requesting $500,000 (direct costs) or more per year, see specific instructions below (Section IV.6, “Other Submission Requirements”).

For the R21 award mechanism, the applicant may request a project period of up to 2 years with a combined budget for direct costs of up $275,000 for the 2-year period. For example, the applicant may request $100,000 in the first year and $175,000 in the second year. The request should be tailored to the needs of the project. Normally, no more than $200,000 may be requested in any single year. See details on the R21 mechanism at http://grants.nih.gov/grants/funding/r21.htm.

Facilities and administrative costs requested by consortium participants are not included in the direct cost limitation, see NOT-OD-05-004.

Section III. Eligibility Information

1. Eligible Applicants

1.A. Eligible Institutions

You may submit (an) application(s) if your organization has any of the following characteristics:

1.B. Eligible Individuals

Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution 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 programs.

2. Cost Sharing or Matching

This program does not require cost sharing as defined in the current NIH Grants Policy Statement at: http://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm#matching_or_cost_sharing.

3. Other-Special Eligibility Criteria
There are no special eligibility criteria for applications submitted in response to this PA.

Section IV. Application and Submission Information

1. Address to Request Application Information

The PHS 398 application instructions are available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. Applicants must use the currently approved version of the PHS 398. For further assistance contact GrantsInfo, Telephone (301) 435-0714, Email: GrantsInfo@nih.gov.

Telecommunications for the hearing impaired: TTY 301-451-5936.

2. Content and Form of Application Submission

Applications must be prepared using the most current PHS 398 research grant application instructions and forms. Applications must have a D&B Data Universal Numbering System (DUNS) number as the universal identifier when applying for Federal grants or cooperative agreements. The D&B number can be obtained by calling (866) 705-5711 or through the web site at http://www.dnb.com/us/. The D&B number should be entered on line 11 of the face page of the PHS 398 form.

The title and number of this funding opportunity must be typed on line 2 of the face page of the application form and the YES box must be checked.

Foreign Organizations

Several special provisions apply to applications submitted by foreign organizations:

Proposed research should provide a unique research opportunity not available in the U.S.

3. Submission Dates and Times
See Section IV.3.A. for details.

3.A. Submission, Review and Anticipated Start Dates

Letter of Intent Submission Date: Not applicable
Application Submission Dates: http://grants.nih.gov/grants/funding/submissionschedule.htm
Peer Review Dates: http://grants.nih.gov/grants/funding/submissionschedule.htm
Council Review Dates: http://grants.nih.gov/grants/funding/submissionschedule.htm
Earliest Anticipated Start Date: http://grants.nih.gov/grants/funding/submissionschedule.htm

3.A.1. Letter of Intent
A letter of intent is not required for the funding opportunity.

3.B. Sending an Application to the NIH

Applications must be prepared using the research grant application forms found in the PHS 398 instructions for preparing a research grant application. Submit a signed, typewritten original of the application, including the checklist, and five signed photocopies in one package to:

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD 20892-7710 (U.S. Postal Service Express or regular mail)
Bethesda, MD 20817 (for express/courier service; non-USPS service)

Personal deliveries of applications are no longer permitted (see http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-040.html).

3.C. Application Processing

Applications must be submitted on or before the application receipt/submission dates described above (Section IV.3.A.) and at http://grants.nih.gov/grants/dates.htm.

Upon receipt applications will be evaluated for completeness by CSR. Incomplete applications will not be reviewed.

The NIH will not accept any application in response to this funding opportunity that is essentially the same as one currently pending initial merit review unless the applicant withdraws the pending application. The NIH will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of a substantial revision of an application already reviewed, but such application must include an Introduction addressing the previous critique.

Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within eight (8) weeks.

4. Intergovernmental Review
This initiative is not subject to intergovernmental review.

5. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.

Pre-Award Costs are allowable. A grantee may, at its own risk and without NIH prior approval, incur obligations and expenditures to cover costs up to 90 days before the beginning date of the initial budget period of a new or competing continuation award if such costs: are necessary to conduct the project, and would be allowable under the grant, if awarded, without NIH prior approval. If specific expenditures would otherwise require prior approval, the grantee must obtain NIH approval before incurring the cost. NIH prior approval is required for any costs to be incurred more than 90 days before the beginning date of the initial budget period of a new or competing continuation award.

The incurrence of pre-award costs in anticipation of a competing or non-competing award imposes no obligation on NIH either to make the award or to increase the amount of the approved budget if an award is made for less than the amount anticipated and is inadequate to cover the pre-award costs incurred. NIH expects the grantee to be fully aware that pre-award costs result in borrowing against future support and that such borrowing must not impair the grantee's ability to accomplish the project objectives in the approved time frame or in any way adversely affect the conduct of the project. See NIH Grants Policy Statement http://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm.

6. Other Submission Requirements

Specific Instructions for Modular Grant applications.

Applications requesting up to $250,000 per year in direct costs must be submitted in a modular budget format. The modular budget format simplifies the preparation of the budget in these applications by limiting the level of budgetary detail. Applicants request direct costs in $25,000 modules. Section C of the research grant application instructions for the PHS 398 at http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-by-step guidance for preparing modular budgets. Applicants must use the currently approved version of the PHS 398. Additional information on modular budgets is available at http://grants.nih.gov/grants/funding/modular/modular.htm.

Specific Instructions for Applications Requesting $500,000 (direct costs) or More per Year.

Applicants requesting $500,000 or more in direct costs for any year must carry out the following steps:

1) Contact the IC program staff at least 6 weeks before submitting the application, i.e., as you are developing plans for the study;

2) Obtain agreement from IC staff that the IC will accept your application for consideration for award; and,

3) Include a cover letter with the application that identifies the staff member and IC who agreed to accept assignment of the application.

This policy applies to all investigator-initiated new (type 1), competing continuation (type 2), competing supplement, or any amended or revised version of these grant application types. Additional information on this policy is available in the NIH Guide for Grants and Contracts, October 19, 2001, at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-004.html.

Plan for Sharing Research Data

The precise content of the data-sharing plan will vary, depending on the data being collected and how the investigator is planning to share the data. Applicants who are planning to share data may wish to describe briefly the expected schedule for data sharing; the format of the final dataset; the documentation to be provided; whether or not any analytic tools also will be provided; whether or not a data-sharing agreement will be required and, if so, a brief description of such an agreement (including the criteria for deciding who can receive the data and whether or not any conditions will be placed on their use); and the mode of data sharing (e.g., under their own auspices by mailing a disk or posting data on their institutional or personal website, through a data archive or enclave). Investigators choosing to share under their own auspices may wish to enter into a data-sharing agreement. References to data sharing may also be appropriate in other sections of the application.

Applicants requesting more than $500,000 in direct costs in any year of the proposed research must include a plan for sharing research data in their application. The funding organization will be responsible for monitoring the data sharing policy (http://grants.nih.gov/grants/policy/data_sharing).

The reasonableness of the data sharing plan or the rationale for not sharing research data may be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or the priority score.

Sharing Research Resources

NIH policy requires that grant awardee recipients make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication (NIH Grants Policy Statement http://grants.nih.gov/archive/archive/grants/policy/nihgps_2003/index.htm and http://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm#_Toc54600131). Investigators responding to this funding opportunity should include a plan for sharing research resources addressing how unique research resources will be shared or explain why sharing is not possible.

The adequacy of the resources sharing plan and any related data sharing plans will be considered by Program staff of the funding organization when making recommendations about funding applications. The effectiveness of the resource sharing will be evaluated as part of the administrative review of each non-competing Grant Progress Report (PHS 2590, http://grants.nih.gov/grants/funding/2590/2590.htm). See Section VI.3. Reporting.

Section V. Application Review Information

1. Criteria
Only the review criteria described below will be considered in the review process.

2. Review and Selection Process

Applications submitted for this funding opportunity will be assigned to the NHLBI, NIA, or NINR on the basis of established PHS referral guidelines.

Appropriate scientific review groups convened in accordance with the standard NIH peer review procedures (http://www.csr.nih.gov/refrev.htm) will evaluate applications for scientific and technical merit.

As part of the initial merit review, all applications will:

The following will be considered in making funding decisions:

The goals of NIH supported research are to advance our understanding of biological systems, to improve the control of disease, and to enhance health. In their written critiques, reviewers will be asked to comment on each of the following criteria in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that an application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward.

Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge or clinical practice be advanced? What will be the effect of these studies on the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Approach: Are the conceptual or clinical framework, design, methods, and analyses adequately developed, well integrated, well reasoned, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics?

Innovation: Is the project original and innovative? For example: Does the project challenge existing paradigms or clinical practice; address an innovative hypothesis or critical barrier to progress in the field? Does the project develop or employ novel concepts, approaches, methodologies, tools, or technologies for this area?

Investigators: Are the investigators appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers? Does the investigative team bring complementary and integrated expertise to the project (if applicable)?

Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed studies benefit from unique features of the scientific environment, or subject populations, or employ useful collaborative arrangements? Is there evidence of institutional support?

2.A. Additional Review Criteria:

In addition to the above criteria, the following items will continue to be considered in the determination of scientific merit and the priority score:

Protection of Human Subjects from Research Risk: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed (see the Research Plan, Section E on Human Subjects in the PHS Form 398).

Inclusion of Women, Minorities and Children in Research: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research will be assessed. Plans for the recruitment and retention of subjects will also be evaluated (see the Research Plan, Section E on Human Subjects in the PHS Form 398).

Care and Use of Vertebrate Animals in Research: If vertebrate animals are to be used in the project, the five items described under Section F of the PHS Form 398 research grant application instructions will be assessed.

2.B. Additional Review Considerations

Budget: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. The priority score should not be affected by the evaluation of the budget.

2.C. Sharing Research Data

Data Sharing Plan: The reasonableness of the data sharing plan or the rationale for not sharing research data may be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or the priority score. The funding organization will be responsible for monitoring the data sharing policy. http://grants.nih.gov/grants/policy/data_sharing.

2.D. Sharing Research Resources

NIH policy requires that grant awardee recipients make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication (See the NIH Grants Policy Statement http://grants.nih.gov/archive/grants/policy/nihgps/part_ii_5.htm#availofrr and http://www.ott.nih.gov/policy/rt_guide_final.html). Investigators responding to this funding opportunity should include a sharing research resources plan addressing how unique research resources will be shared or explain why sharing is not possible.

Program staff will be responsible for the administrative review of the plan for sharing research resources.

The adequacy of the resources sharing plan will be considered by Program staff of the funding organization when making recommendations about funding applications. Program staff may negotiate modifications of the data and resource sharing plans with the awardee before recommending funding of an application. The final version of the data and resource sharing plans negotiated by both will become a condition of the award of the grant. The effectiveness of the resource sharing will be evaluated as part of the administrative review of each non-competing Grant Progress Report (PHS 2590). See Section VI.3. Reporting.

3. Anticipated Announcement and Award Dates
Not applicable

Section VI. Award Administration Information

1. Award Notices

After the peer review of the application is completed, the Principal Investigator will also receive a written critique called a Summary Statement.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant. For details, applicants may refer to the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General (http://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm).

A formal notification in the form of a Notice of Grant Award (NGA) will be provided to the applicant organization. The NGA signed by the grants management officer is the authorizing document. Once all administrative and programmatic issues have been resolved, the Notice of Grant Award will be generated via email notification from the awarding component to the grantee business official (designated in item 14 on the Application Face Page). If a grantee is not email enabled, a hard copy of the Notice of Grant Award will be mailed to the business official.

Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NGA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs. See Also Section IV.5. Funding Restrictions.

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the notice of grant award. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General (http://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm) and Part II Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities (http://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm).

3. Reporting

Awardees will be required to submit the PHS Non-Competing Grant Progress Report, Form 2590 annually (http://grants.nih.gov/grants/funding/2590/2590.htm) and financial statements as required in the NIH Grants Policy Statement.

Section VII. Agency Contacts

We encourage your inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues:

1. Scientific/Research Contacts:

NHLBI
Abby G. Ershow, Sc.D.
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Suite, MSC 7956
Bethesda, MD 20892-7956
Telephone: (301) 435-0550
FAX: (301) 480-2858
Email: ErshowA@mail.nih.gov

Merle Myerson, M.D., Ed.D.
Division of Epidemiology and Clinical Applications
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, MSC 7934
Telephone: (301) 435-1290
FAX: (301) 480-1667
Email: MyersonM@nhlbi.nih.gov

ODS
Rebecca Costello, Ph.D.
Office of Dietary Supplements
National Institutes of Health
6100 Executive Boulevard, Room 3B01, MSC 7517
Bethesda, MD 20892-7517
Telephone: (301) 435-2920
FAX: (301) 480-1845
Email: CostellB@od.nih.gov

NIA
Susan G. Nayfield, M.D., M.Sc.
Geriatrics and Clinical Gerontology Program
National In stitute on Aging
Gateway Building, Suite 3C-307
7201 Wisconsin Avenue 6701
Bethesda, MD 20892-9205
Telephone: (301) 496-6761
FAX: (301) 402-1784
Email: NayfielS@mail.nih.gov

NINR
Karen Huss, R.N., D.N.Sc.
Cardiopulmonary Health and Critical Care Program
Division of Extramural Activities
National Institute of Nursing Research
6701 Democracy Boulevard, Room 710
Bethesda, MD 20892-4870
Telephone: (301) 594-5970
FAX: (301) 480-8260
Email: HussK@mail.nih.gov

2. Peer Review Contacts:
Not applicable

3. Financial or Grants Management Contacts:

NHLBI
Mr. David Reiter
Grants Operations Branch
National Heart, Lung, and Blood Institute
2 Rockledge Center, Room 7142, MSC 7926
6701 Rockledge Drive
Bethesda, MD 20892-7926 (Express 20817)
Telephone: (301) 435-0144
Fax: (301) 480-3310
Email: reiterd@nhlbi.nih.gov

NIA
Mr. John Bladen
Grants and Contracts Management Office
National Institute on Aging
Gateway Building, Suite 2N212
7201 Wisconsin Avenue
Bethesda, MD 20892-9205
Phone: (301) 496-1472
Fax: (301) 402-3672
Email: BladenJ@nia.nih.gov

NINR
Mr. Brian Albertini
Office of Grants and Contracts Management
National Institute of Nursing Research
6701 Democracy Boulevard, Room 710
One Democracy Plaza
Bethesda, MD 20892-4870 (courier use 20817)
Phone: (301) 594-5974
Fax: (301) 402-4502
Email: albertib2@mail.nih.gov

Section VIII. Other Information

Required Federal Citations

Use of Animals in Research:
Recipients of PHS support for activities involving live, vertebrate animals must comply with PHS Policy on Humane Care and Use of Laboratory Animals (http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf) as mandated by the Health Research Extension Act of 1985 (http://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the USDA Animal Welfare Regulations (http://www.nal.usda.gov/awic/legislat/usdaleg1.htm) as applicable.

Human Subjects Protection:
Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained (http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm).

Data and Safety Monitoring Plan:
Data and safety monitoring is required for all types of clinical trials, including physiologic toxicity and dose-finding studies (phase I); efficacy studies (Phase II); efficacy, effectiveness and comparative trials (Phase III). Monitoring should be commensurate with risk. The establishment of data and safety monitoring boards (DSMBs) is required for multi-site clinical trials involving interventions that entail potential risks to the participants (NIH Policy for Data and Safety Monitoring, NIH Guide for Grants and Contracts, http://grants.nih.gov/grants/guide/notice-files/not98-084.html).

Sharing Research Data:
Investigators submitting an NIH application seeking $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible (http://grants.nih.gov/grants/policy/data_sharing).

Investigators should seek guidance from their institutions, on issues related to institutional policies and local IRB rules, as well as local, state and federal laws and regulations, including the Privacy Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the priority score.

Sharing of Model Organisms:
NIH is committed to support efforts that encourage sharing of important research resources including the sharing of model organisms for biomedical research (see http://grants.nih.gov/grants/policy/model_organism/index.htm). At the same time the NIH recognizes the rights of grantees and contractors to elect and retain title to subject inventions developed with federal funding pursuant to the Bayh Dole Act (see the NIH Grants Policy Statement http://grants.nih.gov/archive/archive/grants/policy/nihgps_2003/index.htm). All investigators submitting an NIH application or contract proposal, beginning with the October 1, 2004 receipt date, are expected to include in the application/proposal a description of a specific plan for sharing and distributing unique model organism research resources generated using NIH funding or state why such sharing is restricted or not possible. This will permit other researchers to benefit from the resources developed with public funding. The inclusion of a model organism sharing plan is not subject to a cost threshold in any year and is expected to be included in all applications where the development of model organisms is anticipated.

Inclusion of Women And Minorities in Clinical Research:
It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research” (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines is available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: 1) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and 2) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences.

Inclusion of Children as Participants in Clinical Research:
The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all clinical research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them.

All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects (http://grants.nih.gov/grants/funding/children/children.htm).

Required Education on the Protection of Human Subject Participants:
NIH policy requires education on the protection of human subject participants for all investigators submitting NIH applications for research involving human subjects and individuals designated as key personnel. The policy is available at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

Human Embryonic Stem Cells (hESC):
Criteria for federal funding of research on hESCs can be found at http://stemcells.nih.gov/index.asp and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (http://escr.nih.gov). It is the responsibility of the applicant to provide in the project description and elsewhere in the application as appropriate, the official NIH identifier(s) for the hESC line(s)to be used in the proposed research. Applications that do not provide this information will be returned without review.

Public Access to Research Data through the Freedom of Information Act:
The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are

(1) first produced in a project that is supported in whole or in part with federal funds and (2) cited publicly and officially by a federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this funding opportunity in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award.

Standards for Privacy of Individually Identifiable Health Information:
The Department of Health and Human Services (DHHS) issued final modification to the "Standards for Privacy of Individually Identifiable Health Information," the "Privacy Rule," on August 14, 2002 . The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR).

Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on "Am I a covered entity?" Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

URLs in NIH Grant Applications or Appendices:
All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site.

Healthy People 2010:
The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This PA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople.

Authority and Regulations:
This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. 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 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.

The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

Loan Repayment Programs:
NIH encourages applications for educational loan repayment from qualified health professionals who have made a commitment to pursue a research career involving clinical, pediatric, contraception, infertility, and health disparities related areas. The LRP is an important component of NIH's efforts to recruit and retain the next generation of researchers by providing the means for developing a research career unfettered by the burden of student loan debt. Note that an NIH grant is not required for eligibility and concurrent career award and LRP applications are encouraged. The periods of career award and LRP award may overlap providing the LRP recipient with the required commitment of time and effort, as LRP awardees must commit at least 50% of their time (at least 20 hours per week based on a 40 hour week) for two years to the research. For further information, please see: http://www.lrp.nih.gov.


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NIH Funding Opportunities and Notices


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