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/)

Title: Innovative Technologies for Engineering Small Blood Vessels

Announcement Type
New

Request For Applications (RFA) Number: RFA-HL-05-013

Catalog of Federal Domestic Assistance Number(s)
93.837, 93.839

Key Dates
Release Date: March 3, 2005
Letters of Intent Receipt Date(s): April 18, 2005
Application Receipt Date(s): May 17, 2005
Peer Review Date(s): October- November, 2005
Council Review Date(s) : February 9, 2006
Earliest Anticipated Start Date: April 1, 2006
Expiration Date: May 18, 2005

Due Dates for E.O. 12372
Not Applicable

Additional Overview Content

Executive Summary

The goal of this initiative is to apply recent advances in biomaterials, tissue engineering, and nanotechnology towards the development of small diameter (<5.0 mm inner diameter) functional blood vessels for clinical evaluation. The NHLBI invites applications from investigators interested in developing clinical products for vessel replacement therapy due to cardiovascular disease. This initiative will complement existing programs to apply innovative technologies, tissue engineering and nanofabrication methods, models, and novel biomaterials that overcome barriers toward the development of functional blood vessel substitutes.

The NHLBI intends to commit approximately $15 M for FY 2006-2010 ($2.0 million in FY 06) using the NIH Research Project Grant (R01) mechanism. The total project period for an application in response to this RFA may not exceed five years. Eligible organizations include domestic, for profit and non-profit, public and private, institutions such as universities, colleges and hospitals. Foreign institutions may only participate as subcontractors within a Project Grant. Eligible Principal Investigators are any individual with the skills, knowledge, and resources necessary to carry out the proposed program. Applicants may submit more than one application, provided there is no scientific or budgetary overlap. Applications must be prepared using the PHS 398 application form which can be downloaded at (http://grants.nih.gov/grants/funding/phs398/phs398.html). Telecommunications for the hearing impaired are 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. Receipt and 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
      A. Cooperative Agreement Terms and Conditions of Award
        1. Principal Investigator Rights and Responsibilities
        2. NIH Responsibilities
        3. Collaborative Responsibilities
        4. Arbitration Process
    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

Purpose of this RFA

This Request for Applications (RFA) supports innovative research and technologies to develop small functional blood vessel substitutes for clinical evaluation. For the purposes of this RFA, a small blood vessel is defined as having an internal diameter less than 5 mm. The ultimate outcome for this program is to create an environment that will establish optimal conditions (e.g., cell types, protocols, animal models, and assessment tools) for vessel replacement therapy in humans. Phase I or II human clinical trials should not be included as part of the research plan. Applications are invited from investigators who apply a broad range of multidisciplinary approaches to conduct research and to design, fabricate, and engineer blood vessel substitutes with improved biocompatibility and durability.

Background

Due to the rise in cardiovascular disease throughout the world, there is increasing demand for small diameter blood vessels as replacement grafts. For example, over 300,000 coronary artery bypass graft (CABG) procedures are performed annually in the United States. The use of venous rather than arterial grafts is frequently necessary for one or more vessel replacements, despite a 35% ten-year failure rate for venous grafts as compared to a 10-15% ten-year failure rate for arterial grafts. To combat rising healthcare costs and improve long-term clinical outcomes, technologies are needed to bioengineer vessels functionally similar to native arteries.

In the United States, approximately 200,000 vascular grafting procedures are performed each year in patients with extensive peripheral vascular disease, and in those requiring arteriovenous shunts for hemodialysis. The grafts used for dialysis have only a 50% patency rate at three years and as many as 40% of these grafts develop stenosis that require re-intervention within six months of placement. Such patients would benefit greatly from the availability of biocompatible engineered grafts that offer long term patency.

Small vessel substitutes are needed because existing technologies for large vessel conduits cannot be reproduced for small diameter grafts, and small diameter grafts fail at clinically unacceptable rates. Bioengineered vascular grafts that are capable of remodeling in response to host signals would offer a clear therapeutic benefit in pediatric patients with complex congenital heart diseases. These patients frequently outgrow or quickly occlude their grafts, which are primarily manufactured from synthetic materials.

This RFA is designed to address critical gaps in composition, structure, and mechanical properties needed for blood vessel tissue engineering, as described in the January 2002 World Technology Evaluation Center (WTEC) report. The report is based on findings supported by member agencies of the Multi-Agency Tissue Engineering Science (MATES) Working Group http://www.tissueengineering.gov/. The MATES Working Group includes members from the National Institutes of Health (NIH), National Science Foundation (NSF), National Institute of Standards and Technology (NIST), National Aeronautics and Space Administration (NASA), Defense Advanced Research Projects Agency (DARPA), and the Food and Drug Administration (FDA). In addition, several other forums, such as the 2001 NIH Bioengineering Consortium (BECON) sponsored meeting on "Reparative Medicine: Growing Tissues and Organs" http://www.becon.nih.gov/becon_symposia.htm, recognize the need for improved tissue engineered replacement therapies.

Recent advances in materials science, bioengineering and tissue engineering, along with better computational tools offer unique opportunities to develop replacement blood vessels that closely match the properties of the native vessel. Such properties include, excellent biocompatibility and durability and the ability to self-propagate and self-repair. Accomplishments in nanofabrication methods such as micro- or nano-patterning and electrospinning methods, together with genetic and tissue engineering methods now permit the fabrication of materials with unique and well-defined properties to create hybrid biomaterials that mimic native functional tissues. Similarly, advances in computational tools and imaging have facilitated tissue design and modeling efforts.

Artificial blood vessels are generally constructed from synthetic or xenogenic materials. These grafts place the patients at risk of stenosis, thrombosis, infection, or graft occlusion due to immune response activation. Several strategies have been used to overcome these problems, such as the fabrication of more biocompatible scaffolds using natural or synthetic polymers and applying cell-seeding techniques or chemical coating methods to reduce graft thrombogenicity. Some of these approaches have been tested with limited success in large animal and primate models, including, in rare cases, humans. Mature, systems-level integration to engineer graft vessels with minimal patient risk is lacking.

Objectives and Scope

The goal of tissue engineering and organ fabrication is to create living replacement organs and tissues with the advantages of self-propagation and self-repair. Complex, three-dimensional structures, such as tissue-engineered blood vessels, present many challenges. The purpose of this initiative is to stimulate multidisciplinary groups of investigators that are willing to apply innovative technology and novel methods to bioengineer small (inner diameter less than 5 mm) blood vessels as substitute grafts for clinical application.

An important long-term aim of this initiative is to overcome major roadblocks and barriers in creating tissue engineered products for use by clinicians. This five year program should enable investigators to pursue Phase I/II human clinical trials at the end of the funding period. Applicants are encouraged to identify and refine definitions for evaluative and testing criteria, including validation in animal models that may be required by regulatory agencies. It is expected that applicants funded under this program will interact with and receive guidance from the FDA and other communities, such as the American Society for Testing and Materials (ASTM). Research plans should address manufacturing-related issues such as GMP methods, biomarker monitoring tools, storage, and scaling-up of production in the study design.

Examples might include, but are not limited to:

Applications proposing the following types of studies will be considered non-responsive to the RFA:

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 R01 award mechanism. 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

The NHLBI intends to commit a total of $15 M as follows: approximately $2,000,000 dollars in FY 2006, $3,000,000 in FY 2007, $4,000,000 in FY2008, $3,000,000 in FY 2009, and $3,000,000 in FY 2010 to fund up to three new and/or competing continuation grants in response to this RFA. Applicants may request a project period of up to five years and may not propose more than $400,000 in direct costs for the first year.

This is a one time solicitation. Given the special funding levels approved for this RFA, applicants should execute their milestones in accordance with the escalating and deescalating budget in the out years of this program. Please contact Mr. David Reiter, NHLBI Grants Operations Branch, see Section VII. Agency Contacts, if you have questions about the budget limitations for this program. T he anticipated start date for new awards is approximately April 1, 2006.

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 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. Fiscal and administrative costs are not included in the direct cost limitation, see http://grants.nih.gov/grants/guide/notice-files/NOT-OD-05-004.html.

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:

Applications may be submitted by individual institutions or by consortia of institutions that have pooled their resources to be responsive to the terms of this RFA. It is anticipated that institutions with well-developed and innovative programs in vascular replacement therapy will apply to this announcement. Foreign institutions are not eligible to apply as the primary institution, but may enter into a subcontract with a domestic institution as the primary applicant.

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

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.

3. Other-Special Eligibility Criteria

The overall concept for this program focuses on the challenges and opportunities relevant to developing artificial blood vessels for clinical application. It is expected that applicants will leverage existing knowledge and resources to enable clinical products that can be used in humans.

Bi-annual RFA Meetings: Each Research Project must have a well-delineated organizational structure and administrative mechanism that fosters interaction between industrial and academic scientists and clinicians, which will strengthen the translation of preclinical research findings.

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. 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 PHS 398 research grant application instructions and forms (rev. 5/2001). Applications must have a Dun and 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.

The following headings should appear in the table of contents and in the 25 page research plan in order to facilitate NHLBI review of the responsiveness of each application.

The information pertaining to the headings listed above should be indicated in the Table of Contents. Milestones should not be a restatement of the specific aims or a timeline. Applications lacking this information will be returned to the applicant without review.

3. Submission Dates and Times
Applications must be mailed 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: April 18, 2005
Application Receipt Date(s): May 17, 2005
Peer Review Date: October- November, 2005
Council Review Date: February 9, 2006
Earliest Anticipated Start Date: April 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 NHLBI 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:

Chief, Review Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive
Two Rockledge Centre, Room 7214, MSC 7924
Bethesda, MD 20892-7924
Telephone: (301) 435-0270
FAX: (301) 480-0730
Email: nhlbichiefreviewbranch@nhlbi.nih.gov

3.B. Sending an Application to the NIH

Applications must be prepared using the PHS 398 research grant application instructions and forms as described above. 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)

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

Chief, Review Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive
Two Rockledge Centre, Room 7214, MSC 7924
Bethesda, MD 20892-7924
Telephone: (301) 435-0270
FAX: (301) 480-0730
Email: nhlbichiefreviewbranch@nhlbi.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.

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 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 (see also Section VI.3. Reporting).

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

1. A specific section labeled Project Milestones must be included in the 25 page research plan. Milestones should be well described, quantifiable, and scientifically justified. Applicants should write the milestones assuming that a scientifically literate, non-expert will use them to evaluate the progress that has been achieved. Milestones should not be a restatement of the specific aims or a timeline. The milestones section should be indicated in the Table of Contents. Applications lacking this information will be returned to the applicant without review.

2. To be considered responsive to this announcement, all applications should leverage existing research and resources that will enable the most effective preclinical research. In addition, interactions between academic and industrial scientists are expected to strengthen the research, and enhance the translation of fundamental research findings to the clinical setting. Where appropriate, letters from senior-level individuals describing institutional resource commitment and support must be included.

3. Bi-Annual Grantee Meetings: Each application must have a well-delineated administrative mechanism that fosters interaction between investigators, accelerates the pace of research, and ensures translation of research findings to clinical application. Applications receiving funding under this program should indicate their willingness to participate in twice yearly meetings that will assist with the overall program milestones and progress towards producing effective clinical products. Due to the collaborative nature of this program, the first meeting will require the establishment of a Committee Chair, and members consisting of at least 2 participants from each funded research project, the assigned NHLBI project official, and invited participants from the FDA, ASTM, and officials other interested Agencies. The purpose of the meetings is to encourage the exchange of information among investigators, to ensure that NHLBI has a coherent view of the advances and progress in this program, and to implement procedures which overcome barriers and gaps in the manufacture and assessment of engineered vascular grafts. In the preparation of the budget for the grant application, applicants should include travel funds for two meetings each year, one or both meetings may be held in Bethesda, Maryland. Applicants should also include a statement in their application indicating their willingness to participate in such meetings.

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.

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.

All applicants must include a plan for sharing research data in their application. The data sharing policy is available at http://grants.nih.gov/grants/policy/data_sharing. All investigators responding to this funding opportunity should include a description of how final research data will be shared, or explain why data sharing is not possible.

The reasonableness of the data sharing plan or the rationale for not sharing research data will 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.

Dissemination of Research Results and Intellectual Property Plans for Clinical Products

This initiative encourages investigators to facilitate translating effective interventions and tools into clinical practice. As part of NHLBI's commitment to the rapid translation of research evidence into practice, applicants should include plans for dissemination and/or commercialization of their research and intellectual property plans.

Guidance for Preparation of Sharing Plan and Intellectual Property Plan

This program is expected to lead to knowledge and products of benefit to the public health. The policy of the NIH is to make available to the public the results and accomplishments of the activities that it funds. To address this interest in ensuring research resources are accessible, NIH expects applicants who respond to this RFA to submit a plan: (1) for sharing the research resources generated through the grant (e.g., tissue engineered artificial grafts, biomarker tools that enable vascular graft evaluation); and (2) addressing how they will exercise intellectual property rights, should any be generated through this grant, while making such research resources available to the broader scientific community consistent with this initiative. Therefore, a sharing plan and intellectual property management plans would make unique resources readily available for research purposes to qualified individuals within the scientific community in accordance with the NIH Grants Policy Statement (http://grants.nih.gov/grants/policy/ and the Principles and Guidelines for Recipients of NIH Research Grants and Contracts on Obtaining and Disseminating Biomedical Research Resources: Final Notice, December 1999 http://ott.od.nih.gov/NewPages/64FR72090.pdf) (“NIH Research Tools Guidelines Policy”). These documents also: (1) define terms, parties, and responsibilities; (2) prescribe the order of disposition of rights and a chronology of reporting requirements: and (3) delineate the basis for and extent of government actions to retain rights. Patent rights clauses may be found at 37 CFR Part 401.14 and are accessible from the Interagency Edison web page (http://www.iedison.gov); see also, 35 USC § 210(c); Executive Order 12591, 52 FR 13414 (Apr. 10, 1987); and Memorandum on Government Patent Policy (Feb. 18, 1983). If applicants plan to collaborate with third parties, the research tools sharing plan would need to address how such collaborations would not restrict their ability to share research materials produced with NIH funding. The applicant's institution should avoid exclusively licensing those inventions that are research tools, unless either: (1) the field of use of the exclusive license is restricted to commercial use, or (2) the exclusive licensee will make the research tool available on reasonable terms.

Intellectual property management plans are a just-in-time requirement; it is not necessary to include the final plan approved by all parties in the grant application, but final, approved plans will be expected before a R01 grant can be awarded. NIH program staff will consider the adequacy of the plans in determining whether to recommend an application for award. The approved plans would become a condition of the grant award and Progress Reports must contain information on activities for the sharing of research resources and intellectual property.

In the development of any research resource sharing and intellectual property management plans, applicants should confer with their institutions' office(s) responsible for handling technology transfer related matters and/or sponsored research. The National Heart, Lung, and Blood Institute (NHLBI) views technology transfer as a unique opportunity to expedite the transfer of research results to improve public health while simultaneously establishing collaborative relationships with industry. Applicants may wish to independently contact the NHLBI Office of Technology Transfer and Development web site (http://www.nhlbi.nih.gov/tt/index.htm). The foregoing guidance is provided by way of example to assist applicants in preparing the expected research resources sharing and intellectual property management plans in a manner that encourages partnerships with industry. While these approaches will likely suit most situations, these approaches are not exclusive and applicants should feel free to submit alternative versions for consideration.

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process. As defined in this RFA , only applicants that possess mature capabilities and demonstrate an adequate organizational structure to coordinate and collaborate with key communities that enable clinical product application will continue through review.

The following will be considered in making funding decisions:

2. Review and Selection Process

Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NHLBI. Incomplete and/or non-responsive applications will not be reviewed.

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 the NHLBI in accordance with the review criteria stated below.

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

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.

1. 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?

2. 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? Is the degree to which the organization and leadership of the Project promote and facilitate interactions among key scientific, regulatory, standards, and manufacturing communities adequate? Are the project milestones appropriate and well-defined?

3. 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? Do the vascular graft constructs described in the application offer improvement over existing therapies?

4. 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)? Is the scientific qualifications and involvement of the Project's Principal Investigator, as well as his/her demonstrated scientific and administrative leadership capabilities adequate? Is there adequate time commitment of the Principal Investigator?

5. 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? What is the adequacy of tangible Institutional resources and/or commitments that will enable effective and efficient support of the research project (e.g., facilities, recruitments, discretionary dollars and space)?

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:

Overall Program Organization and Capability

Adequacy of plans to promote and maintain communication and establishing scientific priorities between other projects funded under this program.

Project Milestones

Adequacy of milestones to meet the goals of this RFA. Milestones should be well described, quantifiable, scientifically justified, and match the unique budget restrictions for this program.

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 will 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 presence of a data sharing plan will be part of the terms and conditions of the award. The funding organization will be responsible for monitoring the data sharing policy.

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.

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.

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.

Principal Investigators whose proposals have been selected for award will be notified by post.

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).

The following Terms and Conditions will be incorporated into the award statement and will be provided to the Principal Investigator as well as to the appropriate institutional official, at the time of award.

Project Milestones

Milestones will be agreed to and become part of the terms and conditions of the award. Milestones should be well described, quantifiable, scientifically justified, and match the unique budget restrictions for this program.

Bi-Annual Grantee Meetings

Applicants will be required to participate in Bi-Annual meetings that foster interaction between investigators, accelerates the pace of research, and ensures translation of research findings to clinical application.

Sharing, Dissemination and Intellectual Property Plan

This initiative encourages investigators to facilitate translating effective interventions and tools into clinical practice. As part of NHLBI's commitment to the rapid translation of research evidence into practice, applicants should include plans for dissemination and/or commercialization of their research and intellectual property plans.

3. Reporting

Project Milestones will be agreed to and become part of the terms and conditions of the award. Applicants should write the milestones assuming that a scientifically literate non-expert will use them to evaluate the progress that has been achieved. Milestones should not be a restatement of the specific aims or a timeline.

The following will be considered in making funding decisions:

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:

Heart and Vascular

Martha S. Lundberg, Ph.D.
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 9146
Bethesda, MD 20892-7940
Telephone: (301) 435-0513
FAX: (301) 480-1335
Email: lundberm@mail.nih.gov

Bishow Adhikari, Ph.D.
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 9161
Bethesda, MD 20892-7940
Telephone: (301) 435-0513
FAX: (301) 480-1335
Email: adhikarb@mail.nih.gov

Blood

John Thomas, Ph.D.
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 10154
Bethesda, MD 20892-7950
Telephone: (301) 435-0065
FAX: (301) 451-5453
Email: thomasj@nhlbi.nih.gov

2. Peer Review Contacts:

Chief, Review Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7214
Bethesda, MD 20892-7924
Telephone: (301) 435-0270
FAX: (301) 480-0730
Email: prengerv@mail.nih.gov

3. Financial or Grants Management Contacts:

Mr. David Reiter
Grants Operations Branch
National Heart, Lung, and Blood Institute
2 Rockledge Center, Room 7172, MSC 7926
6701 Rockledge Drive
Bethesda, MD 20892-7926 (Express 20817)
Telephone: (301) 435-0153
Fax: (301) 480-3310
Email: reiterd@nhlbi.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: 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.

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 PA 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/.


Weekly TOC for this Announcement
NIH Funding Opportunities and Notices


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