NHLBI PROGRAMS OF EXCELLENCE IN NANOTECHNOLOGY
 
RELEASE DATE:  March 22, 2004
 
RFA Number:  RFA-HL-04-020  

EXPIRATION DATE: July 22, 2004  

Department of Health and Human Services (DHHS)
 
PARTICIPATING ORGANIZATION:  
National Institutes of Health (NIH)
 (http://www.nih.gov/)

COMPONENT OF PARTICIPATING ORGANIZATION:  
National Heart, Lung, and Blood Institute (NHLBI)
 (http://www.nhlbi.nih.gov/)

CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S) 
93.937, 93.838, 93.839
 
LETTER OF INTENT RECEIPT DATE:  June 23, 2004
APPLICATION RECEIPT DATE:  July 21, 2004
 
THIS RFA CONTAINS THE FOLLOWING INFORMATION

o Purpose of this RFA
o Research Objectives
o Mechanism(s) of Support 
o Funds Available
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Special Requirements 
o Where to Send Inquiries
o Letter of Intent
o Submitting an Application
o Supplementary Instructions
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations

PURPOSE OF THIS RFA 

This RFA will create multidisciplinary teams capable of developing and applying 
nanotechnology and nanoscience solutions to the diagnosis and treatment of 
cardiovascular, pulmonary, hematopoietic and sleep disorders. In recent years, rapid 
advances in science and technology have opened up the burgeoning new field of 
nanotechnology, bringing a myriad of opportunities and possibilities for advancing 
medical science and disease treatment.  Nanotechnology and nanoscience focus on 
materials at the atomic, molecular, and supramolecular levels.  The goal is to 
control and manipulate these new materials by precisely configuring atoms and 
molecules, producing novel molecular assemblies and designing systems of self-
assembly to create supramolecular devices on the scale of an individual cell and 
smaller.  Investigators with skills in nanotechnology rarely focus on heart, lung, 
blood, and sleep (HLBS) research and investigators focused on HLBS disorders are 
generally not oriented to the development and use of nanomaterials and 
nanotechnologies.  Therefore, a crucial need exists to foster partnerships between 
the two communities and to establish shared goals and resources.  Creating 
multidisciplinary teams will be essential to realizing the potential of 
nanotechnology and applying it to HLBS disorders. 
 
RESEARCH OBJECTIVES

Background

Cardiovascular, pulmonary, and blood diseases are responsible for 50% of all deaths 
in the US, killing almost 1.2 million Americans in 1999.  An estimated 61.8 million 
Americans suffer from heart, lung, and blood diseases, resulting in an enormous 
total economic burden of more than $450 billion dollars in 1999.  Nanotechnology and 
nanoscience have the potential to make very significant contributions to the 
diagnosis and therapy of HLBS disorders, mitigating the huge social and economic 
costs of these diseases.  However, the pace of application of nanotechnology and 
nanoscience to HLBS disorders has been slow.  

To accelerate the use of nanotechnology and nanoscience to solve problems in HLBS 
disease, the NHLBI developed a Request for Information (RFI), with advice from 
scientists and physicians with interests in nanotechnology. This RFI canvassed the 
broader scientific community for approaches to developing and applying 
nanotechnology to HLBS disorders.  A Working Group consisting of scientists, 
engineers, and physicians with expertise across nanotechnology, nanoscience, and 
HLBS diseases used the RFI responses as the starting point for their discussions, 
assessing the field of nanotechnology, and suggesting appropriate directions for 
research.  Nanotechnology was broadly construed as research and technology 
development at the atomic and molecular levels intended to create, understand, and 
use nano-scale (i.e., typically less than 100nm) structures, devices, and systems 
having novel properties and functions associated with their size and structure.  In 
addition, the Working Group cautioned against overly rigid or restrictive definition 
of nanotechnology, emphasizing the continuum of scale from the nano- to the micro-
scale.  Nanocomponents will also be important in microscale devices, which are 
therefore included under the nanotechnology rubric. The “top down” approach, 
encompassing miniaturization of current technology, and the “bottom up” approach, 
taking advantage of self-assembly or directed assembly of molecules into 
nanostructures, offer complementary routes for addressing biomedical problems.  

The primary recommendation of the Working Group was to facilitate interdisciplinary 
research between the nanotechnology and nanoscience communities and researchers 
working on HLBS disorders. Therefore this initiative aims to create programs that 
bring together scientists from complementary disciplines through NHLBI Programs of 
Excellence in Nanotechnology (PENs). The PENs will have three goals; i) Perform 
cutting edge research to develop and apply nanotechnology and nanoscience solutions 
to HLBS research and medicine; ii) Develop a cadre of investigators with the ability 
to apply nanotechnology and nanoscience to clinically-oriented HLBS research; iii) 
Disseminate techniques and applications to HLBS research and medicine through 
program websites.  Team members may not necessarily be located in the same 
geographical location, and team size will be determined by the proposed scientific 
problems.  The PENs should be dynamic and able to change and adapt as research and 
the field progress. Inclusion of industrial partners is encouraged in order to 
access the large reserve of expertise available.  The overriding goal of these 
multidisciplinary programs will be to create nanotechnology applications for HLBS 
medicine.  

Research Scope

The potential applications of nanotechnology and nanoscience to clinically relevant 
problems in heart, lung, blood, and sleep disorder research encompass a wealth of 
opportunities.  The diagnosis and treatment of vulnerable atherosclerotic plaque 
represents an area where targeted nanoparticles and nanodevices have great 
potential. Possible applications include noninvasive diagnosis, targeted therapy, 
plaque stabilization by removal of material such as oxidized lipoprotein, and 
nanodevices attaching to unstable plaque and broadcasting external warnings of 
plaque rupture.  Tissue repair and regeneration is another area with broad 
implications for public health where nanotechnology could have great impact, for 
example providing superior scaffoldings for the generation of heart or lung tissue 
or the production of vascular grafts.  Biodegradable nano- and microparticles 
releasing cytokines, growth factors and angiogenic factors have potential for 
guiding tissue repair in vivo.  

Lung inflammatory disease represents another likely target for diagnosis and therapy 
utilizing nanotechnology.  Therapeutic nanoparticles capable of sensing alveolar 
function could release drugs only when needed, restricting drug delivery to affected 
areas in heterogeneous disease conditions. 

Devices to monitor thrombotic and hemorrhagic events are another potential target 
for nanotechnology and nanoscience.  Multifunctional devices could detect events, 
transmit real-time biological data externally, and deliver anticoagulants or 
clotting factors while the patient seeks treatment.

An essential component of developing nanotechnology and nanoscience for HLBS 
medicine will be ensuring that the novel technology is safe to apply.  Biosafety 
(e.g. toxicity, immune responses) should be considered in all applications. 

Hence, the following areas would represent appropriate topics for proposed projects.  
This list is not intended to be all-inclusive, and other topics should be 
considered.

o   Apply nano- and micro-scaffoldings as the basis for tissue repair and cellular 
replacement in vessels and organs.
   
o   Develop multifunctional sensors to detect thrombotic events, transmit real-
time biologic data outside the body and deliver therapeutic agents such as 
anticoagulants as needed.

o   Utilize targeted probes for the detection of vulnerable atherosclerotic plaque 
and targeted delivery of therapy.
   
o   Develop inhaled nanoscale biosensors capable of interrogating lung 
microenvironments, enabling diagnosis of pro-inflammatory signals at an early 
stage.
   
o   Develop nanoparticle-based in vivo sensors to monitor O2 blood concentrations 
and heart functions to detect problems during sleep.
   
o   Utilize lipid-based nanoparticles for site-specific delivery of antifungal or 
other antimicrobial therapy, allowing targeting to the pulmonary epithelium 
and mitigating nephrotoxicity, or directing therapy into bacterial biofilm 
collections.

o   Rationally design genetically engineered proteins for inorganics (GEPIs) – 
proteins engineered to recognize and bind to inorganic molecules, enhancing 
biocompatibility of therapeutic devices. 
   
o   Utilize self-assembling peptide nanotubes to form artificial ion channels with 
regulated function.

It is important to emphasize that the PENs are expected to bring together 
investigators with expertise in nanotechnology and in HLBS research to form 
collaborative programs.

Projects outside the scope of this RFA include;

o   Studies that are not focused on the use of nanotechnology or nanoscience to 
address clinically relevant problems.  While the inclusion of clinical studies 
is not a requirement of the program, technology-driven applications which do 
not include the application of this technology to HLBS biology or disease will 
not be considered responsive.

o   Studies that do not address heart, lung, blood, or sleep disorders.

Program for Skills Development 

Full implementation of a nationwide effort in translational research for 
nanotechnology and nanoscience requires availability of trained M.D., M.D./Ph.D. and 
Ph.D. scientists.  These individuals must be knowledgeable about the molecular 
aspects of nanotechnology and nanoscience and able to integrate the translational 
and clinical concepts necessary for the application of the technology to HLBS 
disorders.  One unique feature of the PENs will be a requirement to function as a 
program for advanced skills development to produce M.D., M.D./Ph.D and Ph.D. 
scientists capable of translational research to apply nanotechnology to HLBS 
disorders.   

MECHANISM OF SUPPORT
 
This RFA will use the NIH U01 award mechanism.  The NIH U01 is a cooperative 
agreement award mechanism. In the cooperative agreement mechanism, the Principal 
Investigator retains the primary responsibility and dominant role for planning, 
directing, and executing the proposed project, with NIH staff being substantially 
involved as a partner with the Principal Investigator, as described under the 
section "Cooperative Agreement Terms and Conditions of Award".  Future unsolicited, 
competing-continuation applications based on this project will compete with all 
investigator-initiated applications and will be reviewed according to the customary 
peer review procedures

FUNDS AVAILABLE 
 
The NHLBI intends to commit approximately $6 million (total costs) in FY 2005 and 
approximately $12 million per year (total costs) in FY2006-9 to fund 3 to 4 new 
grants in response to this RFA. An applicant may request a project period of up to 5 
years, and it is anticipated that a budget for direct costs of up to $1 million for 
FY 2005 and $2 million per year for FY 2006-9 would be appropriate. An additional 
$50,000 per year (direct costs) will be available for the PEN selected to be the 
Administrative Center.  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 RFA are contingent upon the 
availability of funds and the receipt of a sufficient number of meritorious 
applications.  
 
ELIGIBLE INSTITUTIONS
 
You may submit (an) application(s) if your institution has any of the following 
characteristics:
   
o   For-profit or non-profit organizations 
o   Public or private institutions, such as universities, colleges,             
hospitals, and laboratories 
o   Units of State and local governments
o   Eligible agencies of the Federal government  
o   Domestic institutions/organizations
o   Foreign institutions are not eligible to apply as Principal Investigators. 
However, PEN collaborative projects may include work at a foreign site when 
the expertise at the foreign site is not present in the United States.
o   Faith-based or community-based organizations 
 
INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS   

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.   
 
SPECIAL REQUIREMENTS 

Investigator Meetings:  Investigators from the individual PENs will meet annually to 
present updates on progress, to exchange ideas, and to discuss problems encountered.  
The agenda for the meetings will be determined by an Executive Committee comprised 
of the Principal Investigators of the PENs and the NHLBI Program Coordinator.  The 
annual meeting will include poster presentations by postdoctoral fellows as part of 
the skills development program.  The PEN budget should include provisions for 5-10 
investigators to attend the Investigator Meetings.

Executive Committee:  The Executive Committee, comprised of the Principal 
Investigators of the PENs and the NHLBI Program Coordinator, will meet quarterly by 
conference call.  The Executive Committee will plan Investigator Meetings, and 
designate and determine areas of shared interest and potential for collaboration in 
order to further the goals of the program.  The Executive Committee will also 
oversee the Skills Development programs.

Administrative Center: The Administrative Center will serve a range of functions 
common to each PEN such as organizing Investigator Meetings and External Advisory 
Panel meetings, arranging conference calls, and designing and maintaining a website 
to support the PENs.  The Administrative Center site will be selected from the PENs, 
and will receive additional funds to support these activities.  Applicants should 
indicate whether they wish to be considered for the Administrative Center site.

Internal Operating Committee: Each PEN will have an Internal Operating Committee to 
facilitate internal governance and operations, and to oversee the collaborative 
arrangements among investigators.  This Committee should be comprised of the PEN 
Director and component leaders.  The Internal Operating Committee will meet in 
person twice annually, and an NHLBI Program Officer should be present at these 
meetings.

External Advisory Panel: The External Advisory Panel will consist of non-PEN 
affiliated scientists appointed by the NHLBI.  The panel will meet during the second 
and fourth years of the PEN program to review the progress of each PEN, and to 
assess the overall programmatic goals of the initiative. 

Responsiveness:  Technology-driven applications that do not include the application 
of this technology to HLBS biology or disease will not be considered responsive. In 
order to be responsive to the RFA, PENs are required to bring together investigators 
with expertise in nanotechnology and in HLBS research to form collaborative 
programs.
 
Terms and Conditions of Award

The cooperative agreement is an award instrument establishing an Assistance 
relationship (in contrast to an Acquisition relationship) between NHLBI and a 
recipient, in which substantial NHLBI scientific and/or programmatic involvement 
with the recipient is anticipated during performance of the activity.  The NHLBI 
purpose is to support and/or stimulate the recipients’ activity by involvement in 
and otherwise facilitating the activity in a partner role, but avoiding a dominant 
role, direction, or prime responsibility.  The terms and conditions below, elaborate 
on these actions and responsibilities, and the awardee agrees to these collaborative 
actions with the NHLBI Project Scientist toward achieving the project objectives.  
It is anticipated that these terms and conditions will enhance the relationship 
between the NHLBI staff and the principal investigator(s), and will facilitate the 
successful conduct and completion of the study.  These agreements will be in 
addition to, and not in lieu of, the relevant NIH procedures for grants 
administration.  The terms will be as follows:

1. The awardee(s) will have lead responsibilities in all aspects of the study, 
including any modification of study design, conduct of the study, quality control, 
data analysis and interpretation, preparation of publications, and collaboration 
with other investigators, unless otherwise provided for in these terms or by action 
of the Internal Operating Committee and External Advisory Panel.

Internal Operating Committee: Each PEN will have an Internal Operating Committee to 
facilitate internal governance and operations, and to oversee the collaborative 
arrangements among investigators.  This Committee should be comprised of the PEN 
Director and component leaders.  The Internal Operating Committee will meet in 
person twice annually, and an NHLBI Program Officer should be present at these 
meetings.

External Advisory Panel: The External Advisory Panel will consist of non-PEN 
affiliated scientists appointed by the NHLBI.  The panel will meet during the second 
and fourth years of the PEN program to review the progress of each PEN, and to 
assess the overall programmatic goals of the initiative. 

Administrative Center: The Administrative Center will serve a range of functions 
common to each PEN such as organizing Investigator Meetings and External Advisory 
Panel meetings, arranging conference calls, and designing and maintaining a website 
to support the PENs.  

2. The NHLBI Project Scientist will participate in Investigator Meetings; he/she or 
another NHLBI scientist may serve on other study committees, when appropriate.

3.  Awardee(s) agree to oversight by the Executive Committee, comprised of the 
Principal Investigators of the PENs and the NHLBI Program Coordinator. The Executive 
Committee will plan Investigator Meetings, and designate and determine areas of 
shared interest and potential for collaboration in order to further the goals of the 
program.  The Executive Committee will also oversee the Skills Development programs.
 
4. For applications which include clinical components, awardee(s) will submit a data 
and safety monitoring plan. 

5. Awardees will retain custody of and have primary rights to their data developed 
under these awards, subject to Government rights of access consistent with current 
HHS, PHS, and NIH policies.  

6. Support or other involvement of industry or any other third party in the study -- 
e.g., participation by the third party; involvement of study resources or citing the 
name of the study or NHLBI support; or special access to study results, data, 
findings or resources -- may be advantageous and appropriate.  However, except for 
licensing of patents or copyrights, support or involvement of any third party will 
occur only following notification of and concurrence by NHLBI.

7. The NHLBI reserves the right to terminate or curtail the study (or an individual 
award) in the event of (a) substantive changes in the agreed-upon workscope with 
which NHLBI cannot concur, (b) human subject ethical issues that may dictate a 
premature termination.

8. Any disagreement that may arise in scientific/programmatic matters (within the 
scope of the award, between award recipients and the NHLBI) may be brought to 
arbitration.  An arbitration panel will be composed of three members--one selected 
by the Executive Committee (with the NHLBI member not voting) or by the individual 
awardee in the event of an individual disagreement, a second member selected by 
NHLBI, and the third member selected by the two prior members.  This special 
arbitration procedure in no way affects the awardee's right to appeal an adverse 
action that is otherwise appealable in accordance with the PHS regulations at 42 CFR 
part 50, Subpart D and HHS regulation at 45 CFR part 16, or the rights of NHLBI 
under applicable statutes, regulations and terms of the award.

9. These special terms of award are in addition to and not in lieu of otherwise 
applicable OMB administrative guidelines, HHS Grant Administration Regulations at 45 
CFR part 74, and other HHS, PHS, and NIH grant administration policy statements.

WHERE TO SEND INQUIRIES

We encourage inquiries concerning this RFA 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:

o Direct your questions about scientific/research issues to:

Denis Buxton, Ph.D.
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 9044-7940
Bethesda, MD  20892-7940
Bethesda MD 20817 (for express delivery)
Telephone:  (301)435-0516
FAX:  (301)480-1454
Email: buxtond@nhlbi.nih.gov

o Direct your questions about peer review issues to:

Anne P. Clark, Ph.D.
Chief, Review Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
National Institutes of Health
6701 Rockledge Drive, Room 7214, MSC 7924
Bethesda, MD  20892-7924
Bethesda, MD  20817 (for express delivery)
Telephone:  301-435-0270
Fax:    301-480-0730
Email:  clarka@nhlbi.nih.gov

o Direct your questions about financial or grants management matters to:

Norma DeGuzman
Division of Extramural Affairs 
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7167
Bethesda, MD  20892-7926
Telephone:  (301) 496-6740
FAX:  (301) 480-3310
Email: deguzman@nhlbi.nih.gov
 
LETTER OF INTENT
 
Prospective applicants are asked to submit a letter of intent that includes the 
following information:

o Descriptive title of the proposed research
o Name, address, and telephone number of the Principal Investigator
o Names of other key personnel 
o Participating institutions
o Number and title of this RFA 

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 by mail or email to Dr. Anne Clark at 
the address listed under Where to Send Inquiries.

SUBMITTING AN APPLICATION

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 DUNS number can be obtained by calling (866) 705-5711 or 
through the web site at http://www.dunandbradstreet.com/. The DUNS number should be 
entered on line 11 of the face page of the PHS 398 form. The PHS 398 document is 
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.

SUPPLEMENTARY INSTRUCTIONS

1.  Page limitations for PEN applications have been increased to a maximum of 40 
pages from the usual 25-page limit for sections A-D of the "Research Plan". This 40-
page limit is an absolute maximum; standard type size and format specifications must 
be adhered to.  Applicants are encouraged to be concise and use fewer pages.

2.  Description page - In addition to the information requested on Form Page 2, 
identify in the Description the name(s) of the institution(s) leading the PEN and 
other participating institutions.  The Description should clearly indicate the 
area(s) of nanotechnology research that will be the focus of the PEN, the planned 
multi-disciplinary approach, and the specific objective of the project.   

The description of the roles of Lead Investigators should be provided in greater 
detail in the narrative for personnel in the budget section.

The Lead Investigators will usually include the Principal Investigator and a subset 
of the Key Personnel.  The following information is provided to clarify the roles of 
the various individuals who are to be named on this page.  NIH grants policy 
requires that each application designate a single Principal Investigator (PI) who 
(1) is responsible for the overall scientific and technical direction of the effort 
and (2) serves as the contact person with whom NIH staff will interact. Lead 
Investigators provide essential scientific, engineering, technical, and visionary 
leadership to the effort.  Key Personnel are those individuals who contribute in a 
substantive way to the scientific or engineering development or execution of the 
project.

3.  An organization chart that clearly defines the partnership and relationships 
among its various components must be included with the application. A program plan 
should accompany the organization chart and list major tasks with a timeline of 
quantitative milestones for the entire project period. The structure and function of 
the Internal Operating Committee should be described in this section.  The 
organization chart and program plan must not exceed one page each.  This information 
should be included in the Research Design and Methods section of the application.

4.  PEN Budget Items - A separate budget for each partner at a 
subcontract/consortium institution, and when appropriate for clarity, for each 
partner within the grantee institution must be included.  Include a summary budget 
for all PEN participants with partners at non-grantee institutions shown as 
consortium arrangements.  It is understood that this is an initial budget, and that 
the PI has the responsibility, upon approval from NHLBI, to reallocate funds during 
the project to accomplish the PEN goals.

The PI is expected to devote a minimum of 25% effort to the PEN.  The percent effort 
requested for all personnel should be limited to time devoted specifically to PEN 
activities and not to other research projects.  Information documenting the level of 
effort on PEN activities should be included in the application.  The need for all 
requested personnel costs should be thoroughly justified.    

There will be an annual PEN Investigator Meeting at a date and location to be 
determined by NHLBI staff and the Administrative Center.  Applicants should include 
travel funds for 5-10 investigators, including participants in the Skills 
Development Programs, specifically for these meetings in the PEN budget request.  

Applicants may request and justify additional travel funds. Travel funds could be 
used to promote collaboration among PEN partners at different institutions or at a 
distant site, for travel of external advisors to the PEN site, and/or for PEN 
partners to attend scientific meetings essential to the progress of the project and 
for which other funds are not available.

Other expenses can be requested including costs necessary for the central 
administration and fiscal management of the PEN including relevant and reasonable 
costs for reprints, graphics, and publications.  Administrative support (a secretary 
or an administrative assistant) may be requested only for matters directly 
pertaining to the PEN.

With regard to projected funding by source, some PEN applicants may 
anticipate or receive commitments for significant funding from sources other than 
the NIH; e.g., from a collaborating company. In this case, applications should 
describe the source, annual amount, and use of the other funding.

5.  Resources - The application should describe the equipment and facilities 
available for the proposed PEN.

If the PEN entails an institutional commitment of resources across boundaries in the 
institution or anticipates the provision of institutional resources, letters from 
appropriate senior-level individuals describing their agreements to support those 
commitments must be included. 

Where appropriate, describe the shared facilities to be established including 
specific major research instruments and plans for the development of instruments.  
Describe plans for maintaining and operating the facilities including staffing, 
provisions for user fees, and plans for ensuring access to outside users.  
Distinguish between existing facilities and those still to be developed.

6.   Research Design and Methods (Section D of the Research Plan) - A PEN should 
focus on a systems approach for nanotechnology research aimed at a significant 
advance in HLBS medicine.  The research goals should be sufficiently long term and 
comprehensive to justify organizing a PEN and adaptable enough to permit change as 
the research proceeds.   The integrative systems approach and its appropriateness 
for the proposed project should be described including plans for collecting, 
analyzing, and interpreting data.  Plans for enhancing the abilities and 
opportunities for investigators to work across disciplinary boundaries should also 
be included. 
 
7. Skills Development Plan – The Research Design and Methods section of the 
application must include a description of plans to develop interdisciplinary skills 
in postdoctoral fellows and other investigators, and should contain plans for 
mentoring.  The goal of the skills development plan should be to produce independent 
investigators capable of applying nanotechnology and nanoscience to HLBS research 
and medicine.  An investigator with responsibility for overseeing the skills 
development plan should be identified, and the budget for the skills development 
plan should be indicated. A minimum of 5% of the budget should be allocated to the 
skills development plan.  This section is included in the 40 page limit for Sections 
A-D of the Research Plan.

8. Administrative Center – The application should indicate in the Research Design 
and Methods section of the application whether the PEN would be interested in 
serving as the Administrative Center.  The Administrative Center will be selected 
administratively after PEN awards are made, and no application materials are 
required at this time. 

USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) 
application form 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.
 
SENDING AN APPLICATION TO THE NIH: 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
Bethesda, MD  20817 (for express/courier service)
 
At the time of submission, two additional copies of the application must be sent to 
send to Dr. Anne Clark at the address listed under Where to Send Inquiries.
 
APPLICATION PROCESSING: Applications must be received on or before the application 
receipt date listed in the heading of this RFA.  If an application is received after 
that date, it will be returned to the applicant without review. 

Although there is no immediate acknowledgement of the receipt of an application, 
applicants are generally notified of the review and funding assignment within 8 
weeks.
 
The Center for Scientific Review (CSR) will not accept any application in response 
to this RFA 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 an RFA, it is to be prepared as a NEW application.  
That is, the application for the RFA 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.  

PEER REVIEW PROCESS  
 
Upon receipt, applications will be reviewed for completeness by the CSR and 
responsiveness by the NHLBI. Incomplete and/or nonresponsive 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:

o Undergo a process in which only those applications deemed to have the highest 
scientific merit, generally the top half of the applications under review, will be 
discussed and assigned a priority score
o Receive a written critique
o Receive a second level review by the NHLBI Advisory Council. 
 
REVIEW CRITERIA

The goals of NIH-supported research are to advance our understanding of biological 
systems, improve the control of disease, and enhance health.  In the written 
comments, reviewers will be asked to discuss the following aspects of your 
application in order to judge the likelihood that the proposed research will have a 
substantial impact on the pursuit of these goals: 

o Significance 
o Approach 
o Innovation
o Investigator
o Environment
 
The score should reflect the overall impact that the PEN award could have on the 
selected area of HLBS research based on consideration of the five criteria given 
below.  The emphasis on each criterion can vary from one application to another 
depending on the nature of the application and its relative strengths.  An 
application need not be strong in all categories to be judged likely to have major 
technical or scientific impact and thus deserve a high priority score.  For example, 
an investigative partnership may propose to perform important work that by its 
nature is not innovative but is essential to advance a field. 

A PEN may propose design-directed, developmental, discovery-driven, or 
hypothesis-driven research at universities, national laboratories, medical schools, 
large or small businesses, or other public and private entities.
  
The review criteria include:

1. Significance.  If the specific aims of the PEN are achieved, will they provide 
significant advances in the selected area of nanotechnology research? Is the 
research likely to have a significant impact on other areas of research? Will the 
technological advances have a significant impact on human health?

2. Approach.  Are the PEN engineering, scientific, and clinical approaches and 
methods adequately developed, well-integrated, and appropriate to the aims of the 
project?  Does the application address potential problem areas and consider 
alternative strategies?  Is a timetable with adequate research milestones proposed?  
Are appropriate specifications and evaluation procedures provided for assessing 
technological progress? Is the plan for sharing or disseminating technologies 
developed or enhanced under this program announcement adequate? Is the plan for 
technology transfer involving each partnering organization adequate? If partnership 
with industry or small business is included, does this positively affect the 
research goals and technology dissemination?  

3. Innovation.  Does the PEN propose new approaches, explore new research paradigms, 
or represent new concepts that combine engineering, physical, and clinical sciences?  
Will the proposed approaches or concepts solve current scientific or technical 
problems in novel ways?

4. Investigators.  Is the PI capable of coordinating and managing the 
proposed PEN? Are the investigators (partners) appropriately trained in their 
disciplines and capable of conducting and contributing to the management of the 
proposed interdisciplinary work? 

5. Environment.  Does the scientific and technological environment in which the work 
will be done contribute to the probability of success?  Does the proposed research 
take advantage of unique features of the scientific environment or employ useful 
collaborative arrangements within the program?  Is there evidence of institutional 
support?  Does the program create potential opportunities to foster trans-
disciplinary communication and training across traditional scientific and technical 
boundaries?

6. Synergy.  Does the he synergy of aims contribute to the overall goals of the 
project, and are the plans for collaboration between investigators to achieve these 
overall goals adequate?

7.  Skills Development Plan.  Are the skills development plans for developing 
independent investigators who can apply nanotechnology and nanoscience to HLBS 
research and medicine likely to succeed?

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your application will 
also be reviewed with respect to the following:

o BIOSAFETY  Adequacy of plans to address biosafety considerations in order to 
translate the novel technology to the clinical setting.

o DATA SHARING:  Applicants requesting more than $500,000 in direct costs in any 
year of the proposed research must include a data sharing plan in their application. 
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 in the determination of scientific merit or priority 
score.

o BUDGET:  The reasonableness of the proposed budget and the requested period of 
support in relation to the proposed research.

o 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 criteria included in the section on Federal 
Citations, below).
 
o 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.  Plans for the 
recruitment and retention of subjects will also be evaluated. (See Inclusion 
Criteria in the sections on Federal Citations, below).

o 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 398 
research grant application instructions (rev. 5/2001) will be assessed.
  
RECEIPT AND REVIEW SCHEDULE

Letter of Intent Receipt Date:    June 23, 2004
Application Receipt Date:         July 21, 2004
Peer Review Date:                 October/November 2004
Council Review:                     February 2005
Earliest Anticipated Start Date:  April 2005

AWARD CRITERIA

Award criteria that will be used to make award decisions include:

o Scientific merit (as determined by peer review)
o Availability of funds
o Programmatic priorities.
 
REQUIRED FEDERAL CITATIONS 

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).  The establishment of data and safety monitoring boards (DSMBs) 
is required for multi-site clinical trials involving interventions that entail 
potential risk to the participants. (NIH Policy for Data and Safety Monitoring, NIH 
Guide for Grants and Contracts, June 12, 1998: 
http://grants.nih.gov/grants/guide/notice-files/not98-084.html 
 
SHARING RESEARCH DATA:  Starting with the October 1, 2003 receipt date, 
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, 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.

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 - Amended, 
October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 
2001 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); 
a complete copy of the updated Guidelines are 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 RESEARCH INVOLVING HUMAN SUBJECTS: The NIH 
maintains a policy that children (i.e., individuals under the age of 21) must be 
included in all human subjects research, conducted or supported by the NIH, unless 
there are scientific and ethical reasons not to include them. This policy applies to 
all initial (Type 1) applications submitted for receipt dates after October 1, 1998.

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 that is available at 
http://grants.nih.gov/grants/funding/children/children.htm

REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: (if applicable) 
NIH policy requires education on the protection of human subject participants for 
all investigators submitting NIH proposals for research involving human subjects.  
You will find this policy announcement in the NIH Guide for Grants and Contracts 
Announcement, dated June 5, 2000, 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 (see 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). Those who must comply with 
the Privacy Rule (classified under the Rule as “covered entities”) must do so by 
April 14, 2003 (with the exception of small health plans which have an extra year to 
comply).  

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 RFA is related to one or more 
of the priority areas. Potential applicants may obtain a copy of "Healthy People 
2010" at http://www.healthypeople.gov/.

AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal 
Domestic Assistance Nos. 93.937, 93.838, 93.839, and is not subject to the 
intergovernmental review requirements of Executive Order 12372 or Health Systems 
Agency review. Awards are made under authorization of Sections 301 and 405 of the 
Public Health Service Act as amended (42 USC 241 and 284)and administered under NIH 
grants policies described at http://grants.nih.gov/grants/policy/policy.htm and 
under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. 

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.


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