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 Institute on Aging (NIA/NIH), (http://www.nia.nih.gov/)
National Heart, Lung and Blood Institute (NHLBI/NIH), (http://www.nhlbi.nih.gov)

Title: Anemia in the Elderly

Announcement Type
New

Request For Applications (RFA) Number: RFA-AG-06-002

Catalog of Federal Domestic Assistance Numbers
93.866, 93.839

Key Dates
Release Date: August 12, 2005
Letters of Intent Receipt Date(s): December 30, 2005
Application Receipt Dates(s): January 20, 2006
Peer Review Date(s): July 2006
Council Review Date(s): October 2006
Earliest Anticipated Start Date: December 1, 2006
Additional Information To Be Available Date (Url Activation Date): Not applicable
Expiration Date: January 21, 2006

Due Dates for E.O. 12372
Not Applicable

Additional Overview Content

Executive Summary

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. Receipt, 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

 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 goal of this program is to foster biomedical research leading to a better understanding of the epidemiology, pathophysiology, and clinical aspects of anemia in the elderly. Ultimately, information from the research supported by this initiative should improve the health and well-being of elderly patients with anemia and decrease the functional impairment and morbidity associated with anemia in this population.

Background

Anemia is widely recognized as a common clinical finding among the elderly and the most frequently encountered hematologic problem in geriatric practice. Using World Health Organization (WHO) criteria for anemia (hemoglobin concentrations < 12.0 g/dl for women and <13.0 g/dl for men), recent epidemiologic studies report an overall prevalence of anemia of 11.0% of men and 10.2% of women ages 65 years and older who participated in the NHANES-III study and above 20% of participants 85 years of age and older (Guralnik et al, Blood 104:2263, 2004). Of these cases, about one fourth were attributed to “anemia of chronic inflammation (ACI)” with normal iron stores, low circulating iron and often without a clinically apparent underlying chronic disease or inflammatory process. One third of anemias were unexplained by clinical and laboratory findings. Thus over half the cases of anemia in older adults occur without a clearly identifiable cause and thus have no potential therapeutic intervention directed at an underlying condition. This is particularly important because anemia in the elderly has been associated with reduced survival and increased risk of functional decline, cognitive impairment, and death.

Knowledge of the pathophysiology of “unexplained” anemia (UA) in the elderly is generally limited. Changes in hematologic values observed with increasing age include decrease in hemoglobin concentration (g/dl) associated with decreased numbers of erythroid precursors and colony-forming units (CFU-Es) in the bone marrow, consistent with a hypoproliferative state. In addition, a gradual increase in the size (mean cell volume, MCV) of circulating red blood cells in the absence of folate or Vitamin B12 deficiency suggests that ineffective erythropoeisis may be a contributing factor to UA. However, despite these observations, basic mechanisms of these changes in erythroid proliferation, differentiation, and development is largely unexplored.

Recent findings in the area of iron metabolism, particularly the discovery and characterization of hepcidin, have enhanced our understanding of ACI (Ganz et al, Blood 102:783, 2003). Anemia characterized by normal iron stores, low circulating iron, and shortened red cell survival has traditionally been regarded as a consequence of an underlying chronic disease process (“anemia of chronic disease, ACD”). The peptide hormone hepcidin, the dominant regulator (inhibitor) of dietary iron absorption and release of stored iron by macrophages, is decreased by anemia and hypoxia to promote the utilization of iron in RBC production. However, the induction of hepcidin by infection and inflammatory cytokines (e.g., IL-6) and the resulting decrease in circulating iron suggest that ACD may actually represent anemia associated with inflammation (“anemia of chronic inflammation, ACI”). The recognition of elevated levels of inflammatory cytokines in geriatric conditions such as frailty and their association with poor health outcomes emphasizes the need to understand the role of these regulatory factors in anemia as well as in general health and aging processes.

The application of recombinant technology to glycoprotein hormone production has made recombinant erythropoietin (EPO) widely available as a treatment for anemia associated with bone marrow suppression from cancer chemotherapy, chronic renal failure requiring dialysis, and HIV infection. EPO is produced predominantly by the kidney, in response to an oxygen sensor mechanism, to stimulate RBC production to meet tissue oxygen demands. While the role of EPO in UA is yet to be determined, it is hypothesized that inflammation and aging may be associated with decreased (or abnormal) EPO production and/or decreased responsiveness of erythroid precursor cells to EPO. These hypotheses suggest a potential for EPO as a therapy for unexplained anemia in older patients. In addition, the development of new EPO analogs, monoclonal antibodies to IL-6 and other cytokines and their receptors, and small molecules to modulate the enzymatic break-down of HIFá presents new tools and opportunities for exploring molecular mechanisms of UA in the elderly and for translating research findings into clinical applications.

Scientific Knowledge to be Achieved

This initiative supports exploratory and hypothesis-based research on anemia in older patients. To be responsive to this RFA, proposed research projects should have a translational or clinical focus. Basic and mechanistic studies leading directly to translational projects may also be submitted; however, it is the responsibility of the applicant to demonstrate translational relevance.

Examples of research areas and questions include, but are not limited to:

1. Epidemiology/Clinical epidemiology: How are “normal” values of hemoglobin, red cell mass, and EPO defined (statistically, physiologically, functionally, etc.)? How/why do “normal” values vary with age, between genders, and across racial and other defined population subgroups? What is the prevalence and incidence of anemia in older age groups? How does this change across gender and race/ethnicity?

2. Diagnosis: What laboratory parameters should we measure to evaluate anemia? Is hemoglobin the appropriate measure, or should RBC mass or EPO level be used? What are the symptomatology and functional consequences associated with different levels of these measures?

3. Hematopoiesis and hematopoietic reserve: Does the balance of RBC production (“effective” versus “ineffective” hematopoiesis) change with age? Do older persons have the same capacity to respond to anemia with RBC production (“hematopoietic reserve”) as younger persons? How do these potential differences contribute to the pathophysiology of “unexplained” or “idiopathic” anemia in the elderly?

4. Hypoxia/EPO axis: How do EPO levels change with increasing age in the absence of kidney dysfunction? For example, does atherosclerosis decrease renal blood flow and increase hypoxia to raise EPO production? Does this possibility mitigate potential anemia and its frequency in the elderly, or does the hypoxia/EPO axis contribute to “unexplained” anemia in older patients? What is the role of hypoxia-inducing factors (e.g., HIF-á) in modulating these changes?

5. RBC function: Do RBC structural components, function and/or survival change with age? If so, what are the underlying molecular alterations? How do they affect RBC physiology and function, and what is their role in the pathophysiology of “unexplained” anemia in the elderly? What roles do oxidant injury, accumulation of abnormal hemoglobin, mitochondrial dysfunction, and pharmaceuticals play in this process?

6. Inflammation and anemia: What is the role of inflammatory cytokines in anemia of inflammation without clinically apparent inflammatory disease? How much “inflammation” is required to produce the clinical profile of ACI? How do inflammatory cytokines impact hepcidin production and the regulation of iron absorption and uptake and release by macrophages? Why is EPO decreased in this process, and why is EPO administration effective therapy in the presence of decreased response of RBC precursors to EPO?

7. Nutrition: What is the role of nutrient “insufficiency” (rather than “deficiency”) in unexplained anemia in the elderly? How does this relate to other age-related comorbidities (e.g., malabsorption, gastric mucosal atrophy, H. pylori )? When is a trial of iron therapy or oral B12 treatment indicated in UA?

8. Anemia and frailty, fatigue, sarcopenia: What is the role of anemia and/or RBC function in the geriatric symptom complexes of frailty? Of “unexplained” fatigue/exhaustion in older patients without clinically apparent underlying disease? In progressive loss of muscle mass and strength (sarcopenia)?

9. Myelodysplasia: To what extend does myelodysplasia contribute to “unexplained” anemia in the elderly?

10. Therapy: To what extent do comorbidities contribute to UA, and how does their treatment impact the course of anemia and its symptomatology? What constitutes an appropriate clinical evaluation of a patient with UA in the community setting and in the research setting? What is the role of transfusion in the management of UA? Of EPO?

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

Section II. Award Information

1. Mechanisms of Support

This funding opportunity uses the R21, R34, and R01 award mechanisms. As an applicant, you will be solely responsible for planning, directing, and executing the proposed project.

Applications for new exploratory and developmental research projects should use the R21 mechanism described in PA-03-107: “NIH Exploratory and Developmental Research Grant Award (R21)” (see http://grants.nih.gov/grants/guide/pa-files/PA-03-107.html). The applicant may request a project period of up to two years with a combined budget for direct costs of up to $275,000 for the two-year period.

Applicants for R01 investigator-initiated research project awards may request a project period of up to four years and direct costs of up to $350,000 per year.

This RFA will not accept R01 applications for Phase III clinical trials. However, applicants may seek funding for planning Phase III clinical trials in the treatment or prevention of anemia in the elderly. Applications for Clinical Trial Planning Grants should use the R34 mechanism described in PA-04-008: “NIH Clinical Trial Planning Grant (R34) Program” (http://grants.nih.gov/grants/guide/pa-files/PA-04-008.html). The R34 mechanism provides support for the development of a Phase III clinical trial, including the establishment of the research team, the development of tools for data management and oversight of the research, the definition of recruitment strategies, and the finalization of the protocol and procedures manual. Applicants for R34 grants may request a project period of one year and direct costs of up to $100,000.

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, R21 and R34 mechanisms require the modular budget format. if you are submitting an R01 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

NIA and NHLBI intend to commit approximately $2.5 million dollars in FY 2007 to fund four to eight new and/or competing continuation grants in response to this RFA. An applicant for a R01 award may request a project period of up to four years and a budget for direct costs up to $350,000 dollars per year; for a R34 award, a project period of one year and a budget for direct costs up to $100,000 dollars; and, for a R21 award, a project period of up to two years and a budget for direct costs up to $275,000 dollars total over two years.

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 NIA and NHLBI provides 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.

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. The most current Grants Policy Statement can be found at: http://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm#matching_or_cost_sharing.

3. Other-Special Eligibility Criteria
Applicants may submit more than one application, provided they are scientifically distinct.

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 Dun & Bradstreet (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.

3. Submission Dates and Times
Applications must be received on or before the receipt date described below (Section IV.3.A). Submission times N/A.

3.A. Receipt, Review and Anticipated Start Dates

Letter of Intent Receipt Date: December 30, 2005
Application Receipt Date: January 20, 2006
Peer Review Date: July 2006
Council Review Date: October 2006
Earliest Anticipated Start Date: December 1, 2006

3.A.1. Letter of Intent

Prospective applicants are asked to submit a letter of intent that includes the following information:

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.

The letter of intent is to be sent by the date listed at the beginning of this document.

The letter of intent should be sent to:

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

3.B. Sending an Application to the NIH

Applications must be prepared using the research grant applications found in the PHS 398 instructions for preparing a research grant application. Submit a signed, typewritten original of the application, including the checklist, and three 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).

At the time of submission, two additional copies of the application and all appendix material must be sent to:

Dr. Mary Nekola
Chief, Scientific Review Office
National Institute on Aging
Gateway Building, Suite 2C-212
7201 Wisconsin Avenue
Bethesda, MD 20892
Telephone: (301) 496-9666
FAX: (301) 402-0066
Email: nekolam@nia.nih.gov

Using the RFA Label: The RFA label available in the PHS 398 application instructions must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/labels.pdf.

Appendix material should be submitted on a CD following PHS398 instructions for content and format.

3.C. Application Processing

Applications must be received on or before the application receipt date(s) described above (Section IV.3.A.). If an application is received after that date, it will be returned to the applicant without review. Upon receipt, applications will be evaluated for completeness by the CSR and responsiveness by the NIA and NHLBI. Incomplete and non-responsive 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 review, unless the applicant withdraws the pending application. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to a funding opportunity, it is to be prepared as a NEW application. That is, the application for the funding opportunity must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes from the previous unfunded version of the application.

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

Applications for R21 exploratory and developmental grants should follow specific instructions provided in the Program Announcement PA-03-107: “NIH Exploratory/Developmental Research Grant Award (R21)”. This Program Announcement is available online at http://grants.nih.gov/grants/guide/pa-files/PA-03-107.html. However, the number and title of this RFA (Anemia in the Elderly) should be placed in Line 2 on the face page rather than that of PA-03-107.

Applications for R34 clinical trial planning grants should follow specific instructions provided in the Program Announcement PA-04-008: NIH Clinical Trial Planning Grant Award (R34). This Program Announcement is available online at http://grants.nih.gov/grants/guide/pa-files/PA-04-008.html. However, the number and title of this RFA (Anemia in the Elderly) should be placed in Line 2 on the face page rather than that of PA-04-008.

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.

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.

The following will be considered in making funding decisions:

2. Review and Selection Process

Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by NIA in accordance with the review criteria stated below.

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

For applications using the R21 and R01 mechanisms:

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? Regarding translational focus or potential: How will the results of this project contribute to clinical research in anemia in the elderly? If basic research is proposed, how directly will the results of the project support the development of clinical interventions?

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?

For applications using the R34 mechanism:

The NIH R34 is designed to support planning activities in preparation for a full-scale Phase III clinical trial. These activities are primarily logistical, conceptual, and/or technical in nature. They do not involve the collection of data typical of research-related activities supported by the traditional NIH research project grant. As such, the evaluation of R34 applications will focus on the justification of or need for the proposed trial along with the appropriateness of the proposed planning activities (see http://grants.nih.gov/grants/guide/pa-files/PA-04-008.html).

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? Are the significance and need to perform a future full-scale randomized clinical trial (RCT) adequately justified? Would the results of the proposed trial be likely to affect health care policy or practice? Is a planning period necessary? Will the activities planned enhance the development of the future clinical trial? Will the proposed planning period address major barriers to the future clinical trial?

Approach: Are the conceptual framework, design, methods, and analyses, as currently developed, appropriate for the aim of the future RCT? Does the applicant acknowledge potential problem areas and consider alternative tactics?

The reviewers should consider the appropriateness of the intervention(s), selection of endpoints, study population (inclusion/exclusion criteria), randomization schemes, data management, statistical analysis, recruitment and retention plans, and capacity to generalize results. In addition evaluate the adequacy of the activities proposed for the planning period. Will these activities contribute to the likelihood of timely and successful trial implementation? Can these activities be accomplished in the proposed time period? These activities may include, but are not limited to: (a) developing/finalizing the MOP; (b) finalizing plans for addressing gender/minority inclusion and human subjects protection requirements; (c) establishing collaborative arrangements; (d) developing tools needed for data collection and data management; (e) developing/finalizing safety and monitoring plans (applicants are asked not o name individuals for the DSMB but only to include areas of expertise that will be tapped in forming the DSMB); (f) developing plans for Certification Training. Are there adequate plans for the development of an effective organizational structure for carrying out the proposed trial? Are there adequate plans for the development of an essential committee structure, e.g., Steering, Executive, Planning, Data and Safety Committees? Does the application appropriately address issues such as the flow of information to and from the Coordinating Center, to the enrolling centers, and to the appropriate committees?

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: Is the investigator appropriately trained and suited to carry out the proposed trial? Is the work proposed appropriate to the experience level of the Principal Investigator and the research team? Is there clear evidence of leadership? Is there evidence documenting the investigators' ability to plan, organize and manage complex projects?

Environment: Does the scientific environment in which the proposed clinical will be carried out contribute to the probability of success? Will the proposed clinical trial take advantage of the unique features of the scientific environment 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.

Biohazards: If materials or procedures are proposed that are potentially hazardous to research personnel and/or the environment, determine if the proposed protection is adequate.

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 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 Award (NoA) will be provided to the applicant organization. The NoA signed by the grants management officer is the authorizing document. Once all administrative and programmatic issues have been resolved, the NoA 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 NoA 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 NoA 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 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:

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

For NHLBI:
Pankaj Qasba, Ph.D.
Division of Blood Diseases and Resources
NHLBI, NIH, MSC 7950
6701 Rockledge Dr., Room 10161
Bethesda, MD 20892-7950
(use zip code 20817 for courier service)
Phone: 301-435-0084
FAX: 301-480-0868
E-mail: qasbap@nhlbi.nih.gov

2. Peer Review Contacts:

Dr. Mary Nekola
Chief, Scientific Review Office
National Institute on Aging
Gateway Building, Suite 2C-212
7201 Wisconsin Avenue
Bethesda, MD 20892
Telephone: (301) 496-9666
FAX: (301) 402-0066
Email: nekolam@nia.nih.gov

3. Financial or Grants Management Contacts:

Johnny Bladen
Grants and Contracts Management Office
National Institute on Aging
Gateway Building, Suite 2N-212
7201 Wisconsin Avenue
Bethesda, MD 20892
Telephone: (301) 496-1472
FAX: (301) 402-3672
Email: bladenj@nia.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.

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 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.

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: a) 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 b) 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.

NIH Public Access Policy:
NIH-funded investigators are requested to submit to the NIH manuscript submission (NIHMS) system (http://www.nihms.nih.gov) at PubMed Central (PMC) an electronic version of the author's final manuscript upon acceptance for publication, resulting from research supported in whole or in part with direct costs from NIH. The author's final manuscript is defined as the final version accepted for journal publication, and includes all modifications from the publishing peer review process.

NIH is requesting that authors submit manuscripts resulting from 1) currently funded NIH research projects or 2) previously supported NIH research projects if they are accepted for publication on or after May 2, 2005. The NIH Public Access Policy applies to all research grant and career development award mechanisms, cooperative agreements, contracts, Institutional and Individual Ruth L. Kirschstein National Research Service Awards, as well as NIH intramural research studies. The Policy applies to peer-reviewed, original research publications that have been supported in whole or in part with direct costs from NIH, but it does not apply to book chapters, editorials, reviews, or conference proceedings. Publications resulting from non-NIH-supported research projects should not be submitted.

For more information about the Policy or the submission process please visit the NIH Public Access Policy Web site at http://www.nih.gov/about/publicaccess/ and view the Policy or other Resources and Tools including the Authors' Manual (http://www.nih.gov/about/publicaccess/publicaccess_Manual.htm).

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.


Weekly TOC for this Announcement
NIH Funding Opportunities and Notices


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