BIOLOGY OF STEM CELLS IN AGING
 
RELEASE DATE:  October 27, 2003
 
RFA Number:  RFA-AG-04-008

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

COMPONENTS OF PARTICIPATING ORGANIZATIONS:  
National Institute on Aging (NIA)
 (http://www.nia.nih.gov)

CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER: 93.866 
 
LETTER OF INTENT RECEIPT DATE:  December 22, 2003
APPLICATION RECEIPT DATE:  January 22, 2004
 
THIS RFA CONTAINS THE FOLLOWING INFORMATION

o Purpose of this RFA
o Research Objectives
o Mechanisms 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 Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations

PURPOSE OF THIS RFA 

This Request for Applications (RFA) is to solicit applications that 
address the basic biology of stem cells in tissue maintenance and 
disease in aging.  Research to elucidate the role of stem cells in 
tissue turnover, maintenance and repair, and how stem cells and their 
environment change with age, will be important to understanding why 
tissues, organs and organisms experience declining function with age.  
As well, this research will be critical to development of stem-cell 
based therapies for age-related diseases and conditions in the growing 
population of elderly patients. Applications are encouraged for 
projects that significantly advance research to characterize stem cells 
as a function of aging, characterize the tissue environment and the 
interaction of stem cells with that environment during aging, 
understand stem cell involvement in tissue and organ health with age, 
examine how stem cells may integrate into aged tissues for maintenance 
and repair, and examine the role of stem cells in degenerative 
disorders of aging.  Applications may focus on various aging tissues or 
physiological systems, including cardiovascular, musculoskeletal, 
immune, urogenital, endocrine, and nervous systems.   
 
RESEARCH OBJECTIVES

Stem cells are thought to actively maintain a variety of adult tissues, 
such as the intestinal lining, the hematopoietic system, and muscle.  
Recently, the presence of stem cells has been demonstrated in tissues 
not previously known to turn over or be capable of cell replacement, 
such as brain and heart.  The actual role of these stem cells, whether 
circulating or resident in the tissue, in tissue health is not clear, 
and their presence challenges the assumption that some adult tissues 
have little self-renewal capacity.  Disease or age can lead to damage 
to tissue, but elderly individuals are often less able than young 
individuals to repair the tissue, despite the fact that several lines 
of research have indicated that tissue damage stimulates stem cell 
incorporation and repair.  Understanding why stem cells do not appear 
to maintain and repair tissue at a high level of function throughout 
aging is likely to lead to interventions that will enhance the health 
of the elderly.

Work on stem cells indicates that they are involved in tissue 
maintenance in a number of, and perhaps all, tissues.  Age-dependent 
decline in function of stem cells or their progeny in a tissue may 
contribute to physiological decline in function of the tissue.  Both 
the source of these cells and the properties that are needed for the 
cells to maintain their numbers and functions with age are unknown.  
Some work indicates that telomere function or the Wnt pathway may be 
involved in stem cell maintenance and regulation of differentiation in 
several cell types.  Research indicates that stem cells, and the 
progenitor cells derived from them, may be altered such that in some 
tissues fewer fully functional stem and progenitor cells are available 
with age.  It may be that stem cells do not efficiently proliferate, 
migrate, or differentiate appropriately in aged organisms.  Thus, the 
balance of cell types produced by aging stem or progenitor cells may 
change with age and this may be one factor in age-related decline in 
tissue maintenance.  For example, comparatively greater bone resorption 
over bone formation occurs in older animals, apparently as a result of 
changing balance between bone resorbing and bone-building cell types 
derived from the marrow. In some tissues, inappropriate gene sets may 
be turned on in stem cells or their progeny, such as adipocyte gene 
programs in aged muscle satellite cells.  In the aged brain, the ratio 
of new neurons to glial cells that are made from stem cells can change 
depending on the external environment of the old animals.  

There is considerable evidence that the tissue environment changes with 
age.  In a number of tissues the amount of apoptosis increases, leading 
to increased amounts of cell debris and decreased maintenance of the 
immediate environment of the dead cells.  The types and amounts of 
circulating and local cytokines and growth factors change with age.  In 
addition, hormone changes can be either abrupt or gradual.  Change in 
the composition and structure of the extracellular matrix takes place 
with age and with aging-related tissue dysfunction.  The effect of 
these changing environments on stem and progenitor cell function with 
age is not yet known, but could be involved in the gradual decline in 
maintenance of healthy tissues. For example, neural stem cells make 
neurons in certain brain areas due in part to the astroglial cell 
composition of the local environment and this ability of astrocytes to 
instruct stem cells to make neurons appears to decline with age.  It 
would be important, then, to determine if reversal of these 
environmental changes, for example through application of growth 
factors or hormones, could lead to better tissue maintenance or 
healing, and whether the endogenous stem cells in aged tissue are 
capable of fully responding to such changes. The effect of age-related 
changes to the tissue environment needs to be examined in detail to 
understand whether the aged environment is detrimental to stem cells 
and, thus, would interfere with possible stem cell therapies.  The 
safety of stem cell transplantation to the aged tissue environment 
remains an unknown, but is a critical issue since stem-like cells may 
be involved in tumor formation, an event that occurs more frequently in 
aged individuals.

Tissue repair is inhibited with aging in several systems.  For example, 
animal studies show that aged muscle does not recover from periods of 
inactivity as well as young muscle and wound healing is delayed in 
older skin.  The aged or diseased brain is also less conducive to 
regenerative processes.  The role of stem cells in tissue repair is far 
from clear and further work is needed to understand stem cell 
recruitment, differentiation, and integration in aged and damaged 
tissues.   The effect of disease-specific degenerative processes such 
as may occur in Alzheimer’s disease on stem cell properties also need 
to be studied. Bone marrow cells may contribute to the stem cell 
population in tissues, but the processes whereby such cells home to, 
and integrate with, damaged tissues need to be further investigated in 
the context of aging.  Stem cells transplanted to an organism may 
stimulate endogenous repair of defects by influencing local cells, as 
for example in the rescue of dysfunctional dopamine neurons by 
transplanted neural stem cells in the brains of aged mice.  As yet, the 
importance of this effect on tissue repair is unclear.  However, 
effects of transplanted stem cells on endogenous cells or progenitors 
and their environment may be relevant to development of stem cell 
therapies.   Under some conditions, stem cells fuse with other cells, 
though the role of this mechanism in normal tissue repair is unclear.  
Some tissues, such as liver, normally contain many polyploid cells, 
whereas other cells such as Purkinje cells of the cerebellum may fuse 
with bone marrow cells, becoming polyploid.  Whether alterations in the 
processes involved in formation of polyploid cells are associated with 
increased or decreased effectiveness of stem cells in tissue 
maintenance and disease is not clear.  

To deliver on the promise of stem cell research and potential stem cell 
therapies for maintenance of healthy tissues and organs with age, and 
for repair of disease states in the elderly, much additional work is 
needed.  It is clear that much of what is now known about stem cell 
involvement in these processes in young tissues is less well understood 
in the case of aged stem cells, the aged tissue environment, and the 
environment associated with age-related degenerative changes.  
Understanding the changes in populations of aged stem cells, the 
changes in the aged environment and the response of endogenous cells to 
stem cell and hormone or growth factor-stimulated healing are all 
important to maximizing the potential of stem cell-based therapies for 
the elderly.  This population experiences increasing dysfunction and 
disease leading to morbidity and mortality and may be major 
beneficiaries of stem cell research. 

Objectives and Scope

This RFA is intended to encourage basic research into the role of stem 
cells and their progeny in normal tissue aging and in aging changes 
leading to tissue dysfunction and age-related disease.  Only 
applications for projects focused on understanding stem cell biology 
during aging, stem cell involvement in age-related tissue disorders, or 
the aging environment and its influence on stem cell biology are 
appropriate for this RFA.  Projects must have a clear emphasis on aging 
or age-related disease to be accepted for review.  Because this RFA is 
for basic research, projects involving clinical research beyond 
collection of tissues or samples for in vitro use are outside of the 
scope of this announcement.  Applications may focus on various aging 
tissues or physiological systems, including cardiovascular, 
musculoskeletal, immune, urogenital, endocrine, and nervous systems. 
The following examples illustrate areas of research that are of 
interest, but serve as examples only and are not exclusive.  
Prospective applicants are encouraged to discuss possible applications 
with program staff to ensure that they are appropriate to this RFA.

o Research to examine role of stem cells in the balance between cell 
turnover and replacement with age in tissues.

o Research to define stem cell populations, either circulating or 
resident in tissue, and how the populations and properties of stem 
cells change with age.

o Research to understand alternative fates of adult stem cells and how 
these fates may change with age or due to the aged environment.

o Research to define genetic determinants that regulate stem cell 
properties in aging, and how genetic manipulations modify stem cell 
behavior as a function of aging or neurodegenerative processes.

o Research to define factors in the stem cell environment that keep 
them quiescent, self-renewing, or actively repairing tissues; how those 
factors may change with age; and how such changes affect the health of 
the tissue throughout adulthood.

o Research to examine whether cell fusion is a normal and effective 
part of adult stem cell integration into tissues for tissue maintenance 
or repair and whether this process changes with age.

o Research to understand cell-cell interactions between stem cells and 
between stem cells and their environment, such that aged tissue repair, 
either by the stem cells or surrounding cells, is stimulated.

o Research to study the effects of age-related risk factors for tissue 
dysfunction or degeneration, such as oxidative stress, metabolic 
changes, or inflammation, on the properties and function of stem cells.
  
o Research on the role of tissue damage or age-related degenerative 
changes in homing or activation of stem cells for repair, and how this 
may change with age, particularly with respect to effect of changes in 
cytokines or inflammation.

o Research to use growth factors or other molecules to stimulate stem 
cells to migrate and/or repair tissues in response to damage or age-
related dysfunction.  For example, can factors that may be at lowered 
endogenous levels in aged tissue be used to draw stem cells to a 
damaged area and promote their survival and differentiation to replace 
damaged cells?

o Research to examine the role of transplanted stem cells in the 
renewal, rescue, or repair of aged tissues; Research on use of stem 
cells for effective delivery of critical genes or proteins that 
stimulate renewal or repair.

o Research to define the role of self-renewing progenitor cells in age-
related neurodegenerative diseases, such as Alzheimer’s disease.

o Research on the possible role of exhaustion or aging of the stem cell 
pool on longevity.

Potential applicants interested in conducting research on clinical or 
physiologic aspects of stem and progenitor cell number and function in 
humans or in improvements of stem cell assays for such research, are 
encouraged to review the companion NIA RFA (RFA AG-04-009) “Assays of 
Stem Cell Function in Aging Research.”  The full text of this RFA can 
be found on the NIA website for Current Funding Opportunities at 
http://www.nia.nih.gov/data/fundbrowse.asp.

MECHANISMS OF SUPPORT
 
This RFA will use NIH R01 and R21 award mechanisms.  As an applicant 
you will be solely responsible for planning, directing, and executing 
the proposed project.  This RFA is a one-time solicitation.  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. The 
anticipated award date is September 30, 2004. Applications that are not 
funded in the competition described in this RFA may be resubmitted as 
NEW investigator-initiated applications using the standard receipt 
dates for NEW applications described in the instructions to the PHS 398 
application

The R21 is intended to encourage exploratory and developmental research 
projects by providing support for the early and conceptual stages of 
these projects.  Applications for R21 awards should describe projects 
distinct from those supported through the traditional R01 mechanism.  
For example, long-term projects, or projects designed to increase 
knowledge in a well-established area will not be considered for R21 
awards.  Applications submitted under this mechanism should be 
exploratory and novel.  These studies should break 
new ground or extend previous discoveries toward new directions or 
applications.

This RFA uses just-in-time concepts.  It also uses the modular 
budgeting format (see 
http://grants.nih.gov/grants/funding/modular/modular.htm). 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.  

FUNDS AVAILABLE
 
The NIA intends to commit approximately $1.4 Million in FY 2004 to fund 
4 to 7 new grants in response to this RFA. An applicant may request a 
project period of up to 5 years and a budget for direct costs of up to 
$250,000 per year under the R01 mechanism.  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 IC provides 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.  

R21 applications for Exploratory/Developmental Research grants may 
request up to two years of support with a combined budget for direct 
costs of up to $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.  Exploratory/Developmental grant support is for new 
project only; competing continuation applications will not be accepted 
for this mechanism.
 
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 institutions/organizations
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 

It is the intent of the NIA to provide support for stem cell research 
through grant support and through promoting collaboration and 
information sharing between investigators on projects of interest to 
the NIA.  Principal Investigators (PI) on grants resulting from this 
RFA must participate in an annual workshop as convened by the NIA for 
updates and exchange of information related to the projects supported 
by these grants.  In the event the PI is unable to attend, a mutually 
acceptable designee may be agreed upon by the PI and NIA staff to 
participate.  Travel to this annual workshop, expected to be in 
Bethesda, MD, should be included in the budget request in the 
application.
 
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:

Jill L. Carrington, Ph.D.
Chief, Systems Branch
Biology of Aging Program
National Institute on Aging
7201 Wisconsin Avenue, Suite 2C231, MSC 9205
Bethesda, MD   20892-9205
Telephone:  (301) 496-6402
FAX:  (301) 402-0010
Email:  carringtonj@nia.nih.gov

Bradley C. Wise, Ph.D.
Program Director, Fundamental Neuroscience
Neuroscience and Neuropsychology of Aging Program
National Institute on Aging
7201 Wisconsin Avenue, Suite 350 MSC 9205
Bethesda, MD   20892-9205
Telephone:  (301) 496-9350
FAX:  (301) 496-1494
Email: wiseb@nia.nih.gov

o Direct your questions about peer review issues to:

Mary Nekola, Ph.D.
Scientific Review Office
National Institute on Aging
7201 Wisconsin Avenue, Room 2C212 MSC 9205
Bethesda, MD   20892-9205
Telephone:  (301) 496-9666
Email:  nekolam@nia.nih.gov

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

Linda Whipp
Grants and Contracts Management Office
National Institute on Aging
7201 Wisconsin Avenue Suite 2N212 MSC 9205
Bethesda, MD  20892
Telephone:  (301) 496-1472
Email: whippl@nia.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 NIA staff to estimate the potential review 
workload and plan the review.
 
The letter of intent is to be sent by the date listed at the beginning 
of this document.  The letter of intent should be sent to:

Mary Nekola, Ph.D.
Scientific Review Office
National Institute on Aging
7201 Wisconsin Avenue, Room 2C212 MSC 9205
Bethesda, MD   20892-9205
Telephone:  (301) 496-9666
Email:  nekolam@nia.nih.gov

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant 
application instructions and forms (rev. 5/2001). Applications must 
have a DUN and Bradstreet (D&B) Data Universal Numbering System (DUNS) 
number as the Universal Identifier when applying for Federal grants or 
cooperative agreements. The 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.
 
SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications 
requesting up to $250,000 per year in direct costs 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.

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 and 
all copies of the appendix material must be sent to:

Mary Nekola, Ph.D.
Scientific Review Office
National Institute on Aging
7201 Wisconsin Avenue, Room 2C212 MSC 9205
Bethesda, MD   20892-9205
Telephone:  (301) 496-9666
Email:  nekolam@nia.nih.gov

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 NIA. 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 NIA 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 National Advisory Council on 
Aging 
 
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 evaluate 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 the following 
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 have major scientific impact and thus deserve a high 
priority score.  For example, an investigator may propose to carry out 
important work that by its nature is not innovative but is essential to 
move a field forward.

SIGNIFICANCE: Does this study address an important problem? If the aims 
of the application are achieved, how will scientific knowledge 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:

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 AND MINORITIES IN RESEARCH: The adequacy of plans to 
include subjects from both genders and all racial and ethnic groups 
(and subgroups) 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).

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.

RECEIPT AND REVIEW SCHEDULE

Letter of Intent Receipt Date:  December 22, 2003
Application Receipt Date:  January 22, 2004
Peer Review Date:  May 2004
Council Review:  September 2004
Earliest Anticipated Start Date:  September 30, 2004

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 

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.

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://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 RFA 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 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.

Return to Volume Index

Return to NIH Guide Main Index

	Office of Extramural Research (OER)			National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892			Department of Health and Human Services (HHS)
Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, RealPlayer, Video or Flash files, see Help Downloading Files.