NIGMS EXPLORATORY STUDIES FOR HIGH IMPACT/HIGH RISK RESEARCH

RELEASE DATE:  April 8, 2003

PA NUMBER:  PA-03-100 (Effective March 2, 2006, applications will 
                       no longer be accepted by NIGMS in response to this PA. 
                       See, NOT-GM-06-002) 

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. 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 thereafter. Applications relating to R33 and R34 
activities must be in response to NIH Institute/Center (IC)-specific announcements.

EXPIRATION DATE: March 2, 2006

National Institute of General Medical Sciences (NIGMS)
 (http://www.nigms.nih.gov) 

CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S): 93.309, 93.821, 93.859, 93.862

THIS PA CONTAINS THE FOLLOWING INFORMATION

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

PURPOSE OF THIS PA  

The purpose of this PA is to re-announce the National Institute of General 
Medical Sciences (NIGMS) program to support exploratory, high impact/high 
risk research last issued as PA-97-049 in March of 1997.  This program 
attempts to broaden the base of inquiry in fundamental biomedical research by 
encouraging applications for research projects that involve an especially 
high degree of innovation and novelty, such that their potential for highly 
significant outcomes may be difficult to judge by the standard criteria used 
in evaluating R01 proposals.  Research projects proposed under this program 
may lack preliminary data establishing feasibility, but should present the 
opportunity for conceptual or technological breakthroughs. 

RESEARCH OBJECTIVES

The National Institute of General Medical Sciences (NIGMS) seeks to encourage 
fundamental research projects that fall into the following classes: projects 
to test novel and significant hypotheses for which there is scant precedent 
or preliminary data and which, if confirmed, would have a substantial impact 
on current thinking; projects to explore a new experimental organism or 
system in order to address particularly difficult basic biomedical questions 
for which the new system would be particularly advantageous; projects to 
develop innovative techniques or methodologies with wide applicability to the 
study of basic biomedical problems.
 
The projects must support the NIGMS mission as detailed in the publication, 
"Divisions and Grant Award Mechanisms," available from the NIGMS Public 
Information Office (301/496-7301); additional information can be found on the 
NIGMS World Wide Web home page at www.nigms.nih.gov.  In brief, NIGMS 
supports research in (a) cell biology and molecular biophysics, including 
basic studies of the structure and function of cells, cellular components, 
and the biological macromolecules that make up these components;(b) 
fundamental mechanisms of inheritance and development that typically utilize 
non-human model systems; (c) basic studies in pharmacology, physiology, 
biochemistry, bio-related chemistry and anesthesiology;(d) research in 
bioinformatics and computational biology, basic studies in biotechnology and 
metabolic engineering; (e) development and refinement of bioanalytical 
methods and instrumentation; and (f) trauma and burn injury.

MECHANISM(S) OF SUPPORT 

This PA will use the NIH Exploratory/Developmental Research Grant (R21) award 
mechanism.  As an applicant, you will be solely responsible for planning, 
directing, and executing the proposed project. 

You 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, you 
may request $100,000 in the first year and $175,000 in the second year. The 
request should be tailored to the needs of your project.  Normally, no more 
than $200,000 may be requested in any single year.  Requests for the full 
amount will require rigorous justification.  NIGMS expects to make most 
awards for less than the maximum amount. 

This PA uses just-in-time concepts.  It also uses the modular budgeting 
format. (see http://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 
http://grants.nih.gov/grants/policy/nihgps_2001/part_i_1.htm.  

Exploratory/developmental grant support is for 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 
http://grants.nih.gov/grants/policy/amendedapps.htm.  If appropriate, the 
specific aims of the R21 project may be incorporated into a research project 
grant application (R01) submitted prior to the termination of the R21 award.

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 or foreign
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. 

WHERE TO SEND INQUIRIES

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:

Dr. James C. Cassatt
Division of Cell Biology and Biophysics
National Institute of General Medical Sciences
Building 45, Room 2AS.19C, MSC 6200
Bethesda, MD  20892-6200
Telephone: (301) 594-0828
FAX: (301) 480-2004
email: cassattj@nigms.nih.gov 
 
Dr. Marcus Rhoades
Division of Genetics and Developmental Biology
National Institute of General Medical Sciences
Building 45, Room 2AS.25M, MSC 6200
Bethesda, MD  20892-6200
Telephone: (301) 594-0943
FAX: (301) 480-2228
Email: rhoadesm@nigms.nih.gov 
 
Dr. Michael E. Rogers
Division of Pharmacology, Physiology and Biological Chemistry
National Institute of General Medical Sciences
Building 45, Room 2AS.49C
Bethesda, MD  20892
Telephone: (301) 594-3827
FAX: (301) 480-2802
email: rogersm@nigms.nih.gov 
 
o Direct your questions about financial or grants management matters to:

Mr. Joe Ellis
Grants Management Officer
National Institute of General Medical Sciences
Building 45, Room 2AN.32C, MSC6200
Bethesda, MD  20892-6200
Telephone: (301) 594-5135
FAX: (301) 480-1969
email: ellisj@nigms.nih.gov 

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001).  The PHS 398 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.

On the face page of the application, check "Yes" and type the number of this 
program announcement on line 2.

APPLICATION RECEIPT DATES:  Applications submitted in response to this 
program announcement will be accepted at the standard application deadlines, 
which are available at http://grants.nih.gov/grants/dates.htm.  Application 
deadlines are also indicated in the PHS 398 application kit.

SUPPLEMENTAL 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 are required but may be included if 
available.  Please note that a Progress Report is not needed; competing 
continuation applications for an exploratory/developmental grant will be not 
accepted.

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

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications must be 
submitted in a modular grant format.  The modular 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 http://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 
http://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 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)

APPLICATION PROCESSING: Applications must be mailed on or before the three 
standard receipt dates described at 
http://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 application already reviewed, but 
such application must include an Introduction addressing the previous 
critique.

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

PEER REVIEW PROCESS

Applications submitted for this PA will be assigned on the basis of 
established PHS referral guidelines.  An appropriate scientific review group 
convened by the CSR 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 Receive a written critique
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 second level review by the National Advisory General Medical 
Sciences Council

REVIEW CRITERIA

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 background material 
or preliminary information as one might normally expect in an R01 
application.  Accordingly, reviewers will focus their evaluation on the 
conceptual framework, the level of innovation, and the potential to 
significantly advance our knowledge or understanding.  Reviewers will 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 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 scientific review group will address and consider each of these criteria 
in assigning your application's overall score, weighting them as appropriate 
for each application.  The 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 be advanced?  
What will be the effect of these studies on the concepts or methods that 
drive this field?

(2) 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?   

(3) 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? 

(4) 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)?

(5) 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:  

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.)
 
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 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.  

ADDITIONAL CONSIDERATIONS 
 
DATA SHARING:  The adequacy of the proposed plan to share data. 

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

AWARD CRITERIA

Applications submitted in response to a 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

The following additional factors will be considered for applications 
submitted in response to this program announcement and assigned to NIGMS:

o Potential for ground-breaking, precedent-setting significance of the 
proposed research, with particular emphasis on novel and innovative 
approaches that clearly require additional preliminary data for their value 
to be established.

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.

MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components 
involving Phase I and II clinical trials must include provisions for 
assessment of patient eligibility and status, rigorous data management, 
quality assurance, and auditing procedures.  In addition, it is NIH policy 
that all clinical trials require data and safety monitoring, with the method 
and degree of monitoring being commensurate with the risks (NIH Policy for 
Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 
1998: http://grants.nih.gov/grants/guide/notice-files/not98-084.html).  

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: 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://grants.nih.gov/grants/stem_cells.htm 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 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 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.

Weekly TOC for this Announcement
NIH Funding Opportunities and Notices

	Office of Extramural Research (OER)			National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892			Department of Health and Human Services (HHS)
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