RELEASE DATE:  September 16, 2003

PA NUMBER:  PA-03-171

March 2, 2006  (NOT-OD-06-046) – Effective with the June 1, 2006 submission date, 
all R03, R21, R33 and R34 applications must be submitted through Grants.gov using
the electronic SF424 (R&R) application. This announcement will stay active for only 
the May 1, 2006 AIDS and AIDS-related application submission date. The non-AIDS
portion of this funding opportunity expires on the date indicated below. Parent 
R03 (PA-06-180) and R21 (PA-06-181) funding opportunity announcements have been 
issued for the submission date of June 1, 2006 and submission dates for AIDS and 
non-AIDS applications thereafter. Applications relating to R33 and R34 activities 
must be in response to NIH Institute/Center (IC)-specific announcements.

EXPIRATION DATE for R21 Non-AIDS Applications: March 2, 2006
EXPIRATION DATE for R21 AIDS and AIDS-Related Applications: May 2, 2006 

Department of Health and Human Services (DHHS)


National Institutes of Health (NIH)


National Heart, Lung, and Blood Institute (NHLBI) 
Office of Rare Diseases (ORD)



o Purpose of the PA
o Research Objectives
o Mechanism of Support 
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Where to Send Inquiries
o Submitting an Application
o Supplementary Instructions
o Peer Review Process
o Review Criteria
o Award Criteria
o Required Federal Citations


The purpose of this announcement is to define the scope of exploratory and 
developmental grant applications to the National Heart, Lung, and Blood Institute 
(NHLBI) for support of investigators with novel approaches to understanding, 
treating, and preventing rare diseases in the areas of heart, lung, and blood 
disease as well as sleep disorders. The Office of Rare Diseases at NIH (ORD) will 
co-fund applications in these rare diseases.  Availability of R21 awards for these 
individuals is expected to allow investigators with novel ideas to obtain research 
support without the need for large amounts of preliminary data that often serves as 
a barrier to entry into the NIH grants system.  It is anticipated that these 
efforts will ultimately result in an increased pipeline of therapeutic approaches 
to treatment and prevention of rare diseases.  Such diseases are often referred to 
as "orphan" diseases since there is a general lack of interest among industries to 
invest resources in diseases that in aggregate comprise too small a population to 
guarantee return on investment. Potential applicants may wish to review the 
information available through the Office of Rare Diseases 
http://rarediseases.info.nih.gov/. The R21 is intended to encourage exploratory 
and developmental research projects by providing support for the early and 
conceptual stages of projects dealing with heart, lung, and blood diseases and 
sleep disorders.


The National Institutes of Health has received a substantial increase in research 
funding from Congress for the purpose of expanding the national investment of the 
United States in behavioral and biomedical research. Notwithstanding such 
increases, funding for rare diseases and disorders at the National Institutes of 
Health has not increased appreciably. The Rare Disease Act of 2002 (Public Law 107-
280) established the Office of Rare Diseases to encourage collaboration and new 
research endeavors for rare diseases. For these reasons and because of the number 
of such diseases in the areas of heart, lung, and blood disease along with sleep 
disorders, the NHLBI and ORD invite applications utilizing the R21 funding 
mechanism in the area of rare diseases.

The R21 mechanism is intended to encourage new exploratory and developmental 
research projects.  Such projects should be designed to provide preliminary results 
to demonstrate feasibility of novel approaches to heart, lung, and blood diseases 
and sleep disorders.  Studies may involve considerable risk with the expectation 
that the results to be obtained lead to a breakthrough in a particular area, or to 
the development of novel techniques, agents, methodologies, or approaches that 
could have major impact reducing the burden of rare diseases in the areas of 
cardiovascular, respiratory, and blood disease.  New activities that promote the 
formation of new research collaborations and explore novel approaches to test 
imaginative new ideas while providing preliminary data to demonstrate concept 
feasibility are especially encouraged. Potential areas of application could include 
but are not limited to the following:

o Heart and Vascular Diseases: arrhythmogenic right ventricular dysplasia, 
Brugada's Syndrome, congenital heart disease, familial homozygous 
hypercholesterolemia, Liddle's Syndrome, Long QT Syndrome.
o Lung Diseases: alpha1-antitrypsin deficiency, berylliosis, bronchopulmonary 
dysplasia, Churg-Strauss Syndrome, cystic fibrosis, LAM, primary pulmonary 
fibrosis, sarcoidosis.
o Blood Diseases: aplastic anemias, the hemophilias, hereditary, hemorrhagic 
telangiectasia, lymphatic diseases, myelodysplastic syndromes, myeloproliferative 
disorders, sickle cell disease, stem cell therapies for rare diseases such as 
inborn errors of metabolism, the thalassemias, the thrombocytopenias.
o Sleep Disorders: congenital central hypoventilation syndrome (Ondine's Curse), 
circadian rhythm disorders such as advanced sleep phase syndrome.

Applicants responding to this PA must use the NIH Exploratory/ Developmental 
Research Grant (R21) award mechanism.  The applicant will be solely responsible for 
planning, directing, and executing the proposed project. Guidelines for this 
mechanism are available at 

The applicant may request a project period of up to two years with a combined 
budget for direct costs of up $275,000 for the two year period.  For example, the 
applicant may request $100,000 in the first year and $175,000 in the second year.  
The request should be tailored to the needs of the project. Normally, no more than 
$200,000 may be requested in any single year.  Each new investigator will be solely 
responsible for planning, directing, and executing the proposed research.  

This PA uses just-in-time concepts.  It also uses the modular budgeting format. 
(see https://grants.nih.gov/grants/funding/modular/modular.htm).   All applications 
submitted in response to this announcement must use the modular budget format.  
This program does not require cost sharing as defined in the current NIH Grants 
Policy Statement at 

Under this PA exploratory/developmental grant support is for new investigators with 
new projects only; competing continuation applications will not be accepted.   Two 
revisions of a previously reviewed exploratory/developmental grant application may 
be submitted as defined in NIH Policy at 


You may submit an application if your institution has any of the following 
o For-profit or non-profit organizations 
o Public or private institutions, such as universities, colleges, hospitals, and 
o Units of State and local governments
o Eligible agencies of the Federal government  
o Domestic or foreign institutions/organizations
o Faith-based or community-based organizations 


Any investigator with the skills, knowledge, and resources necessary to carry out 
the proposed research is eligible to serve as the principal investigator of an 
award through this program.  Investigators representing underrepresented racial and 
ethnic groups as well as those with disabilities are always encouraged to apply for 
NIH programs.  


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

o Direct your questions about scientific/research issues to:

David A. Lathrop, Ph.D.
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 9142 (MSC 7940)
Bethesda, MD 20892-7940 (20817 for Courier)
Telephone: (301) 435-0529
FAX: (301) 480-1454
Email: LathropD@nhlbi.nih.gov

Elizabeth L. Wagner, M.P.H.
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 10159 (MSC 7950)
Bethesda, MD 20892-7950 (20817 for Courier)
Telephone: (301) 435-0065
FAX: (301) 480-0868
Email: WagnerE@nhlbi.nih.gov

Mary Beth Clark
Division of Epidemiology and Clinical Applications
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 8108 (MSC 7938)
Bethesda, MD 20892-7938 (20817 for Courier)
Telephone: (301) 435-0405
FAX: (301) 480-1864
Email: ClarkM@nhlbi.nih.gov

Giovanna M. Spinella, M.D.
Director, Extramural Research Program
Office of Rare Diseases, OD, NIH
6100 Executive Blvd.  Rm. 3B01-MSC 7518
Bethesda, MD 20892-7518
Telephone:  301 402-4336
Fax:  301 480-9655
E-mail:  spinellg@od.nih.gov

Carol E. Vreim, Ph.D.
Division of Lung Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 10120 (MSC 7952)
Bethesda, MD 20892-7952 (20817 for Courier)
Telephone: (301) 435-0233
FAX: (301) 480-3547
Email: VreimC@nhlbi.nih.gov

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

Kieran Kelley
Grants Operations Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7156, MSC 7926
Bethesda, Maryland 20892-7926
Telephone: (301) 435-0171
FAX: (301) 480-3310
Email: KelleyK2@mail.nih.gov


Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001).  Applications must have a Dun and Bradstreet 
number (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 thr PHS 398 form.  The PHS 398 is available at 
https://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive 
format.  For further assistance contact GrantsInfo, Telephone (301) 710-0267, 
Email: GrantsInfo@nih.gov.

APPLICATION RECEIPT DATES:  Beginning with the October 1, 2003 receipt date, 
applications submitted in response to this program announcement will be accepted at 
the standard application deadlines, which are available at 
https://grants.nih.gov/grants/dates.htm.  Application deadlines are also indicated 
in the PHS 398 application kit.

SUPPLEMENTARY INSTRUCTIONS:  All instructions for the PHS 398 (rev. 5/2001) must be 
followed, with these exceptions:

o  Research Plan

Items a - d of the Research Plan (Specific Aims, Background and Significance, 
Preliminary Studies, and Research Design and Methods) may not exceed a total of 15 
pages.  No preliminary data is required but may be included if it is available.  
Because competing continuation applications for an exploratory/developmental grant 
are ineligible and will not be accepted, a Progress Report may not be included.

Appendix.  Use the instructions for the appendix detailed in the PHS 398 except 
that no more than 5 manuscripts, previously accepted for publication, may be 

initiated R21 applications must be submitted in a modular budget grant format.  The 
modular budget grant 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 (rev. 5/2001) at 
https://grants.nih.gov/grants/funding/phs398/phs398.html includes step-by-step 
guidance for preparing modular grants.  Additional information on modular grants is 
available at https://grants.nih.gov/grants/funding/modular/modular.htm.

SENDING AN APPLICATION TO THE NIH:  Submit a signed, typewritten original of the 
application, including the checklist, and five signed photocopies in one package 

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)

APPLICATION PROCESSING: Applications must be received by or mailed on or before the 
receipt dates described at 
https://grants.nih.gov/grants/funding/submissionschedule.htm.  The CSR will not 
accept any application in response to this PA that is essentially the same as one 
currently pending initial review unless the applicant withdraws the pending 
application.  The CSR will not accept any application that is essentially the same 
as one already reviewed.  This does not preclude the submission of a substantial 
revision of an unfunded version of an application already reviewed, but such 
application must include an Introduction addressing the previous critique.

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


Applications submitted for this PA will be assigned on the basis of established PHS 
referral guidelines.  Appropriate scientific review groups, convened  in accordance 
with the standard NIH peer review procedures http://www.csr.nih.gov/refrev.htm), 
will evaluate applications for scientific and technical merit.  

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

o Undergo a selection process in which only those applications deemed to have the 
highest scientific merit, generally the top half of applications under review, will 
be discussed and assigned a priority score
o Receive a written critique
o Receive a second level review by the appropriate national advisory council or 

The NIH R21 exploratory/developmental grant is a mechanism for supporting novel 
scientific ideas or new model systems, tools or technologies that have the 
potential to significantly advance our knowledge or the status of health-related 
research.  Because the research plan is limited to 15 pages, an 
exploratory/developmental grant application need not have extensive background 
material or preliminary information as normally expected in an R01 application.  
Reviewers will be instructed to focus their evaluation on the conceptual framework, 
the level of innovation, and the potential to significantly advance our knowledge 
or understanding.  Reviewers will thus place less emphasis on methodological 
details and certain indicators traditionally used in evaluating the scientific 
merit of R01 applications including supportive preliminary data. Appropriate 
justification for the proposed work can be provided through literature citations, 
data from other sources, or, when available, from investigator-generated data.  
Preliminary data are not required for R21 applications.    
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 the 
application in order to judge the likelihood that the proposed research will have a 
substantial impact on the pursuit of these goals. The scientific review group will 
address and consider each of these criteria in assigning the application's overall 
score, weighting them as appropriate for each application.  

o Significance 
o Approach 
o Innovation
o Investigator
o Environment

The application does not need to be strong in all categories to be judged likely to 
significantly advance current knowledge and thus deserve a meritorious priority 
score.  For example, an investigator may propose to carry out important work that 
by its nature is not innovative but is essential to move a field forward.

SIGNIFICANCE: Does this study address an important problem? If the aims of the 
application are achieved, how will scientific knowledge be advanced? What will be 
the effect of these studies on the concepts or methods that drive this field?

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

INNOVATION: Does the project employ novel concepts, approaches or methods? Are the 
aims original and innovative? Does the project challenge existing paradigms or 
develop new methodologies or technologies?

INVESTIGATOR: Is the investigator 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 (if any)?

ENVIRONMENT: Does the scientific environment in which the work will be done 
contribute to the probability of success? Do the proposed experiments take 
advantage of unique features of the scientific environment or employ useful 
collaborative arrangements? Is there evidence of institutional support?  

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

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).
include subjects of either gender, 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 Inclusion Criteria in the sections on Federal Citations, below).

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.  


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


Applications submitted in response to this PA will compete for available funds with 
all other recommended applications.  The following will be considered in making 
funding decisions:  

o Scientific merit of the proposed project as determined by peer review
o Availability of funds 
o Relevance to program priorities


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.

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 participants.  (NIH Policy for Data Safety and Monitoring, NIH 
Guide for Grants and Contracts, June 12, 1998: 

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 

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 https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html; 
a complete copy of the updated Guidelines are available at 
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.

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, 

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 

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 

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  
https://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. 

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 

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.

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 https://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 

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.

Weekly TOC for this Announcement
NIH Funding Opportunities and Notices

Office of Extramural Research (OER) - Home Page Office of Extramural
Research (OER)
  National Institutes of Health (NIH) - Home Page National Institutes of Health (NIH)
9000 Rockville Pike
Bethesda, Maryland 20892
  Department of Health and Human Services (HHS) - Home Page Department of Health
and Human Services (HHS)
  USA.gov - Government Made Easy

Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files.